Boron-containing small molecules

ABSTRACT

Compounds, pharmaceutical formulations, and methods of treating bacterial infections are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application of U.S. application Ser. No.16/081,902, filed Sep. 1, 2018, which is a national phase application ofInternational Patent Application No. PCT/US2017/019650, filed Feb. 27,2017, which claims the benefit of U.S. Provisional Patent ApplicationNo. 62/302,564, filed Mar. 2, 2016, which is incorporated by referencein its entirety for all purpose.

BACKGROUND OF THE INVENTION

The present invention relates to organic compounds, such aspleuromutilins. Pleuromutilin, a compound having the following formula:

is a naturally occurring antibacterial, e.g. produced by thebasidomycetes Pleurotus mutilus and P. passeckerianus, see e.g. TheMerck Index, 13th edition, item 7617. Further modified pleuromutilinsare also known.

Surprisingly, it has now been discovered that certain classes ofpleuromutilins modified with boron are surprisingly effectiveantibacterials. This, and other uses of these compounds, are describedherein.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound having a structurewhich is a salt or a hydrate or a solvate thereof, having a structurewhich is:

wherein X is H or F or OH; Y is selected from the group consisting of abond, —O—, —S—, —NH—, substituted or unsubstituted alkylene, andsubstituted or unsubstituted heteroalkylene; and Z is a substituted orunsubstituted heterocyclic ring or ring system containing at least oneendocyclic boron.

In a second aspect, the invention provides a combination comprising acompound of the invention together with at least one othertherapeutically active agent.

In a third aspect, the invention provides a pharmaceutical formulationcomprising: a) a compound of the invention; and b) a pharmaceuticallyacceptable excipient.

In a fourth aspect, the invention provides a method of inhibitingprotein synthesis in a bacteria, the method comprising contacting thebacteria with a compound of the invention, thereby inhibiting proteinsynthesis in the bacteria.

In a fifth aspect, the invention provides a method of inhibiting thegrowth and/or killing a bacteria, the method comprising contacting thebacteria with the compound of the invention, thereby inhibiting thegrowth and/or killing the bacteria.

In a sixth aspect, the invention provides a method of treating amicrobial disease and/or a worm disease in an animal, the methodcomprising administering to the animal a therapeutically effectiveamount of a compound of the invention, thereby treating the microbialdisease and/or the worm disease.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: Ac is acetyl; AcOH is aceticacid; ACTBr is cetyltrimethylammonium bromide; AIBN isazobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Aris aryl; B₂pin₂ is bis(pinacolato)diboron; Bn is, in general, benzyl[see Cbz for one example of an exception]; (BnS)₂ is benzyl disulfide;BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc istert-butoxy carbonyl; Boc₂O is di-tert-butyl dicarbonate; Bz is, ingeneral, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z isbenzyloxycarbonyl or carboxybenzyl; Cs₂CO₃ is cesium carbonate; CSA iscamphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy iscyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM isdichloromethane or methylene chloride; DHP is dihydropyran; DIAD isdiisopropyl azodicarboxylate; DIEA or DIPEA isN,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate;EtOH is ethanol; Et₂O is diethyl ether; EDCI isN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; ELS isevaporative light scattering; equiv or eq is equivalent; h is hours;HATU is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is hydrochloricacid; HPLC is high pressure liquid chromatography; ISCO Companion isautomated flash chromatography equipment with fraction analysis by UVabsorption available from Presearch; KOAc or AcOK is potassium acetate;K₂CO₃ is potassium carbonate; LiAlH₄ or LAH is lithium aluminum hydride;LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithiumhydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methylcyanide or cyanomethane or ethanenitrile or acetonitrile which are allnames for the same compound; MeOH is methanol; MgSO₄ is magnesiumsulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH₃ issodium cyanoborohydride; NaOH is sodium hydroxide; Na₂SO₄ is sodiumsulfate; NBS is N-bromosuccinimide; NH₄Cl is ammonium chloride; NIS isN-iodosuccinimide; N₂ is nitrogen; NMM is N-methylmorpholine; n-BuLi isn-butyllithium; overnight is O/N; PdCl₂(pddf) is1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is thecatalyst known as palladium on carbon; Pd₂(dba)₃ is an organometalliccatalyst known as tris(dibenzylideneacetone) dipalladium(0); Ra Ni orRaney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is1-propanol; iPrOH is 2-propanol; POCl₃ is phosphorus chloride oxide;PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used hereinmeans Pyridine; RT or rt or r.t. is room temperature; sat. is saturated;Si-amine or Si—NH₂ is amino-functionalized silica, available fromSiliCycle; Si-pyr is pyridyl-functionalized silica, available fromSiliCycle; TEA or Et₃N is triethylamine; TFA is trifluoroacetic acid;Tf₂O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAAis trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI istrimethylsilyl iodide; H₂O is water; diNO₂PhSO₂Cl is dinitrophenylsulfonyl chloride; 3-F-4-NO₂-PhSO₂Cl is 3-fluoro-4-nitrophenylsulfonylchloride; 2-MeO-4-NO₂-PhSO₂Cl is 2-methoxy-4-nitrophenylsulfonylchloride; and (EtO)₂POCH₂COOEt is a triethylester of phosphonoaceticacid known as triethyl phosphonoacetate.

“Compound of the invention,” as used herein, refers to the compoundsdiscussed herein, salts (e.g. pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

“Combination of the invention,” as used herein, refers to the compoundsand antiinflammatories discussed herein as well as acids, bases, saltforms (such as pharmaceutically acceptable salts), prodrugs, solvatesand hydrates of these compounds and antiinflammatories.

“Boron containing compounds”, as used herein, refers to the compounds ofthe invention that contain boron as part of their chemical formula.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to theremainder of the molecule.

The symbol

whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The term “alkenylene” by itself or as part of another substituent meansa divalent radical derived from an alkene.

The term “cycloalkylene” by itself or as part of another substituentmeans a divalent radical derived from a cycloalkane.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from an heteroalkane.

The term “heterocycloalkylene” by itself or as part of anothersubstituent means a divalent radical derived from an heterocycloalkane.

The term “arylene” by itself or as part of another substituent means adivalent radical derived from an aryl.

The term “heteroarylene” by itself or as part of another substituentmeans a divalent radical derived from heteroaryl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of B, O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) B, O, N andS may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S— CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S— CH₂—CH₂— and —CH₂—S— CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 or 2 or 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR′″″—C(NR′R″R′″)═NR″″, —NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R′, R″, R′″,R′″″ and R′″″ each preferably independently refer to hydrogen,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, e.g., aryl substituted with 1-3 halogens, substituted orunsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.When a compound of the invention includes more than one R group, forexample, each of the R groups is independently selected as are each R′,R″, R′″, R″″ and R′″″ groups when more than one of these groups ispresent. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include, but not be limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″,—NR″″—C(NR′R″)═NR″″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 or 6 or 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5- to 7-membered ring” includes, for examplephenyl, pyridinyl and piperidinyl. The term “5- to 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N), sulfur(S), silicon (Si), germanium (Ge), aluminum (Al) and boron (B).

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of an active agent to provide the desired local orsystemic effect. A “Topically effective,” “pharmaceutically effective,”or “therapeutically effective” amount refers to the amount of drugneeded to effect the desired therapeutic result.

“Topically effective” refers to a material that, when applied to theskin, nail, hair, claw or hoof produces a desired pharmacological resulteither locally at the place of application or systemically as a resultof transdermal passage of an active ingredient in the material.

The term “pharmaceutically acceptable salt” is meant to include a saltof a compound of the invention which is prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino (suchas choline or diethylamine or amino acids such as d-arginine,1-arginine, d-lysine, 1-lysine), or magnesium salt, or a similar salt.When compounds of the invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein readilyundergo chemical changes under physiological conditions to provide thecompounds of the invention. Additionally, prodrugs can be converted tothe compounds of the invention by chemical or biochemical methods in anex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the invention. Certain compounds of the invention may exist inmultiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and brokenwedges are used to denote the absolute configuration of a stereocenterunless otherwise noted. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms areincluded.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If, for instance, a particular enantiomer of acompound of the invention is desired, it can be prepared by asymmetricsynthesis, or by derivatization with a chiral auxiliary, where theresulting diastereomeric mixture is separated and the auxiliary groupcleaved to provide the pure desired enantiomers. Alternatively, wherethe molecule contains a basic functional group, such as an amino group,or an acidic functional group, such as a carboxyl group, diastereomericsalts can be formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). The compounds may also be labeled with stableisotopes such as deuterium. All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the animal. Representative carriers include water, oils,both vegetable and mineral, cream bases, lotion bases, ointment basesand the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the pharmaceutical arts. Additional information concerningcarriers can be found in Remington: The Science and Practice ofPharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which isincorporated herein by reference.

The term “pharmaceutically acceptable additive” refers to preservatives,antioxidants, fragrances, emulsifiers, dyes and excipients known or usedin the field of drug formulation and that do not unduly interfere withthe effectiveness of the biological activity of the active agent, andthat is sufficiently non-toxic to the animal. Additives for topicalformulations are well-known in the art, and may be added to the topicalcomposition, as long as they are pharmaceutically acceptable and notdeleterious to the epithelial cells or their function. Further, theyshould not cause deterioration in the stability of the composition. Forexample, inert fillers, anti-irritants, tackifiers, excipients,fragrances, opacifiers, antioxidants, gelling agents, stabilizers,surfactant, emollients, coloring agents, preservatives, bufferingagents, other permeation enhancers, and other conventional components oftopical or transdermal delivery formulations as are known in the art.

The term “excipients” is conventionally known to mean carriers,diluents, vehicles, and or additives used in formulating drugcompositions effective for the desired use.

The terms “effective amount” or a “therapeutically effective amount” ofa drug or pharmacologically active agent refers to a nontoxic butsufficient amount of the drug or agent to provide the desired effect. Inthe oral dosage forms of the present disclosure, an “effective amount”of one active of the combination is the amount of that active that iseffective to provide the desired effect when used in combination withthe other active of the combination. The amount that is “effective” willvary from subject to subject, depending on the age and general conditionof the individual, the particular active agent or agents, and theappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The phrases “active ingredient”, “therapeutic agent”, “active”, or“active agent” mean a chemical entity which can be effective in treatinga targeted disorder, disease or condition.

The phrase “pharmaceutically acceptable” means moieties or compoundsthat are, within the scope of medical judgment, suitable for use inhumans without causing undesirable biological effects such as unduetoxicity, irritation, allergic response, and the like, for example.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule. This is a single unit. In some embodiments, the dosage formincludes a compound of the invention as part of a therapeuticallyeffective dosage of a cream or ointment. This is also a single unit. Insome embodiments, the dosage form includes a compound of the inventionand another active ingredient contained within one capsule, or as partof a therapeutically effective dosage of a topical formulation, such asa cream or an ointment, for example. This is a single unit, whether ornot the interior of the capsule includes multiple discrete granules ofthe active ingredient. In some embodiments, the dosage form includes acompound of the invention in one capsule, and the active ingredient in asecond capsule. This is a two unit dosage form, such as two capsules ortablets, and so such units are contained in a single package. Thus theterm ‘unit’ refers to the object which is administered to the animal,not to the interior components of the object.

The term, “prodrug”, as defined herein, is a derivative of a parent drugmolecule that exerts its pharmacological effect only after chemicaland/or enzymatic conversion to its active form in vivo. Prodrugs includethose designed to circumvent problems associated with delivery of theparent drug. This may be due to poor physicochemical properties, such aspoor chemical stability or low aqueous solubility, and may also be dueto poor pharmacokinetic properties, such as poor bioavailability or poorhalf-life. Thus, certain advantages of prodrugs may include improvedchemical stability, absorption, and/or PK properties of the parentcarboxylic acids. Prodrugs may also be used to make drugs more amenableto the animal, by minimizing the frequency (e.g., once daily) or routeof dosing (e.g., oral), or to improve the taste or odor if given orally,or to minimize pain if given parenterally.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Inhibiting” and “blocking,” are used interchangeably herein to refer tothe partial or full blockade of an enzyme, such as a beta-lactamase or aleucyl t-RNA synthetase or a phosphodiesterase.

Boron is able to form additional covalent or dative bonds with oxygen,sulfur or nitrogen under some circumstances in this invention.

Embodiments of the invention also encompass compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof.

“Salt counterion”, as used herein, refers to positively charged ionsthat associate with a compound of the invention when the boron is fullynegatively or partially negatively charged. Examples of salt counterionsinclude H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium, organic amino(such as choline or diethylamine or amino acids such as d-arginine,1-arginine, d-lysine, 1-lysine), and sodium.

The compounds comprising a boron bonded to a carbon and threeheteroatoms (such as three oxygens described in this section) canoptionally contain a fully negatively charged boron or partiallynegatively charged boron. Due to the negative charge, a positivelycharged counterion may associate with this compound, thus forming asalt. Examples of positively charged counterions include H⁺, H₃O⁺,ammonium, potassium, calcium, magnesium, organic amino (such as cholineor diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine,1-lysine), and sodium. These salts of the compounds are implicitlycontained in descriptions of these compounds.

II. Introduction

The invention provides novel boron compounds and methods for thepreparation of these molecules. The invention further provides methodsof treating bacterial infections, killing and/or inhibiting the growthof bacteria in part or wholly through the use of the compounds describedherein. In another aspect, the invention is a combination of a compoundof the invention and an antibacterial. In another aspect, the inventionis a pharmaceutical formulation comprising a pharmaceutically acceptableexcipient and a compound of the invention. In another aspect, theinvention is a pharmaceutical formulation comprising a compound of theinvention, an antibacterial, and a pharmaceutically acceptableexcipient.

III. a) Compounds

In one aspect the invention provides a compound of the invention. In anexemplary embodiment, the invention provides a compound describedherein, or a salt or a hydrate or a solvate thereof. In an exemplaryembodiment, the salt of a compound described herein is apharmaceutically acceptable salt. In an exemplary embodiment, theinvention provides a compound described herein, or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the inventionprovides a compound described in a formula provided herein. In anexemplary embodiment, the invention provides a compound describedherein.

In an exemplary embodiment, the compound has a structure which is

wherein X is H or F or OH; Y is selected from the group consisting of abond, —O—, —S—, —NH—, substituted or unsubstituted alkylene, andsubstituted or unsubstituted heteroalkylene; and Z is a substituted orunsubstituted heterocyclic ring or ring system containing at least oneendocyclic boron.

In an exemplary embodiment, the compound is Formula (I), Y and Z are asdescribed herein, and X is H. In an exemplary embodiment, the compoundis Formula (I), Y and Z are as described herein, and X is F. In anexemplary embodiment, the compound is Formula (I), Y and Z are asdescribed herein, and X is OH.

In an exemplary embodiment, the compound is Formula (I), X and Z are asdescribed herein, and Y is substituted alkylene. In an exemplaryembodiment, the compound is Formula (I), X and Z are as describedherein, and Y is unsubstituted alkylene. In an exemplary embodiment, thecompound is Formula (I), X and Z are as described herein, and Y ismethylene. In an exemplary embodiment, the compound is Formula (I), Xand Z are as described herein, and Y is ethylene. In an exemplaryembodiment, the compound is Formula (I), X and Z are as describedherein, and Y is propylene. In an exemplary embodiment, the compound isFormula (I), X and Z are as described herein, and Y is substitutedheteroalkylene. In an exemplary embodiment, the compound is Formula (I),X and Z are as described herein, and Y is unsubstituted heteroalkylene.In an exemplary embodiment, the compound is Formula (I), X and Z are asdescribed herein, and Y is *—OCH₂—. In an exemplary embodiment, thecompound is Formula (I), X and Z are as described herein, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), X andZ are as described herein, and Y is *—NHCH₂—. In an exemplaryembodiment, the compound is Formula (I), X and Z are as describedherein, and Y is *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), X and Z are as described herein, and Y is *—C(O)NH—. In anexemplary embodiment, the compound is Formula (I), X and Z are asdescribed herein, and Y is *—CH₂NHCH₂— or 1-piperazinyl or *—S(O)CH₂— or*—S(O)₂—. In an exemplary embodiment, the compound is Formula (I), X andZ are as described herein, and Y is 1-piperazinyl. In an exemplaryembodiment, the compound is Formula (I), X and Z are as describedherein, and Y is *—S(O)CH₂—. In an exemplary embodiment, the compound isFormula (I), X and Z are as described herein, and Y is *—S(O)₂—. In anexemplary embodiment, the compound is Formula (I), X and Z are asdescribed herein, and Y is *—NHC(O)OCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and Z is substituted or unsubstituted heteroaryl,wherein said heteroaryl comprises an endocyclic boron. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, and Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has one ring, and said ring comprises an endocyclic boron. Inan exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and Z is substituted or unsubstituted heteroaryl,wherein said heteroaryl has two rings, and one of the two ringscomprises an endocyclic boron.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl comprises an endocyclicboron. In an exemplary embodiment, the compound is Formula (I), X and Yare as described herein, and Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has one ring, and saidring comprises an endocyclic boron. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has two rings, and one of the two rings comprises anendocyclic boron.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and Z is substituted or unsubstituted benzoxaborole.In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and Z is substituted or unsubstitutedpyridinyloxaborole. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, and Z is substituted orunsubstituted benzoxaborininol. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, and Z is substituted orunsubstituted benzoxazaborininol. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, and Z issubstituted or unsubstituted benzodiazaborininol. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, and Z is substituted or unsubstituted oxaborole. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, and Z is substituted or unsubstituted dihydrobenzoazaborinine.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁴, R⁵, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁴, R⁶, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, the compound is Formula (I), R⁴, R⁵, R⁶, R⁷,X and Y are as described herein, Z is Formula (II) or (III), and R³ is Hand R^(3a) is H. In an exemplary embodiment, the compound is Formula(I), R⁴, R⁵, R⁶, R⁷, X and Y are as described herein, Z is Formula (II)or (III), and R³ is unsubstituted C₁-C₃ alkyl and R^(3a) isunsubstituted C₁-C₃ alkyl. In an exemplary embodiment, the compound isFormula (I), R⁴, R⁵, R⁶, R⁷, X and Y are as described herein, Z isFormula (II) or (III), and R³ is unsubstituted C₁-C₃ alkyl and R^(3a) isH. In an exemplary embodiment, the compound is Formula (I), R⁴, R⁵, R⁶,R⁷, X and Y are as described herein, Z is Formula (II) or (III), and R³is methyl and R^(3a) is methyl. In an exemplary embodiment, the compoundis Formula (I), R⁴, R⁵, R⁶, R⁷, X and Y are as described herein, Z isFormula (II) or (III), and R³ is methyl and R^(3a) is H. In an exemplaryembodiment, the compound is Formula (I), R⁴, R⁵, R⁶, R⁷, X and Y are asdescribed herein, Z is Formula (II) or (III), and R³ is C₁-C₃ alkylsubstituted with substituted or unsubstituted amino and R^(3a) is H. Inan exemplary embodiment, the compound is Formula (I), R⁴, R⁵, R⁶, R⁷, Xand Y are as described herein, Z is Formula (II) or (III), and R³ is—CH₂NH₂ and R^(3a) is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H or halogen, R⁵is H or halogen, and R⁷ is H or halogen. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (II), R⁴ is halogen, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is Cl, R⁵ is H, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), R³, R^(3a), X andY are as described herein, Z is Formula (II), R⁴ is F, R⁵ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (II), R⁴ is H, R⁵is halogen, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(II), R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (II), R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is H, R⁵ is H, and R⁷ ishalogen. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (II), R⁴ is H, R⁵is H, and R⁷ is Cl. In an exemplary embodiment, the compound is Formula(I), R³, R^(3a), X and Y are as described herein, Z is Formula (II), R⁴is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(II), R⁴ is H, R⁵ is halogen, and R⁷ is halogen. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is H, R⁵ is Cl, and R⁷ is Cl. Inan exemplary embodiment, the compound is Formula (I), R³, R^(3a), X andY are as described herein, Z is Formula (II), R⁴ is H, R⁵ is F, and R⁷is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H or halogen,R⁶ is H or halogen, and R⁷ is H or halogen. In an exemplary embodiment,the compound is Formula (I), R³, R^(3a), X and Y are as describedherein, Z is Formula (III), R⁴ is halogen, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), R³, R^(3a), X and Yare as described herein, Z is Formula (III), R⁴ is Cl, R⁶ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (III), R⁴ is F, R⁶is H, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), R³, R^(3a), X and Y are as described herein, Z is Formula (III), R⁴is H, R⁶ is halogen, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (III), R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (III), R⁴ is H, R⁶ is F, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), R³, R^(3a)X and Yare as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, and R⁷ ishalogen. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (III), R⁴ is H, R⁶is H, and R⁷ is Cl. In an exemplary embodiment, the compound is Formula(I), R³, R^(3a), X and Y are as described herein, Z is Formula (III), R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(III), R⁴ is H, R⁶ is halogen, and R⁷ is halogen. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (III), R⁴ is H, R⁶ is Cl, and R⁷ is Cl.In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is F, andR⁷ is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H or cyano, R⁵is H or cyano, and R⁷ is H or cyano. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (II), R⁴ is cyano, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is H, R⁵ is cyano, and R⁷ is H.In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is cyano.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H or cyano, R⁶is H or cyano, and R⁷ is H or cyano. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (III), R⁴ is cyano, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (III), R⁴ is H, R⁶ is cyano, and R⁷ is H.In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is cyano.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴, R⁵, and R⁷ areeach independently selected from H or C₁-C₃ alkyl substituted withamino. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (II), R⁴, R⁵, andR⁷ are each independently selected from H or —CH₂NH₂. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), R³, R^(3a),X and Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is—CH₂NH₂, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(II), R⁴ is H, R⁵ is H, and R⁷ is —CH₂NH₂.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴, R⁶, and R⁷ areeach independently selected from H or C₁-C₃ alkyl substituted withamino. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (III), R⁴, R⁶, andR⁷ are each independently selected from H or —CH₂NH₂. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (III), R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), R³, R^(3a),X and Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is—CH₂NH₂, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(III), R⁴ is H, R⁶ is H, and R⁷ is —CH₂NH₂.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴, R⁵, and R⁷ areeach independently selected from H or C₁-C₃ alkoxy. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴, R⁵, and R⁷ are eachindependently selected from H or —OCH₃. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), X and Y are as described herein, Zis Formula (II), R⁴ is —OCH₃, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), R⁴ is H, R⁵ is —OCH₃, and R⁷ is H.In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is —OCH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴, R⁶, and R⁷ areeach independently selected from H or C₁-C₃ alkoxy. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (III), R⁴, R⁶, and R⁷ are eachindependently selected from H or —OCH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is —OCH₃, R⁶is H, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is —OCH₃,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is —OCH₃,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is H, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is —OCH₃, R⁶ isH, and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),Y is as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a)is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is—OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—OCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is —OCH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is —OCH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is—OCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is—OCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (III), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is—OCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is H, Z is Formula (III), R³ is CH₃,R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is F, Z is Formula (III), R³ isCH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H,R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁶ is H, andR⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁶ isH, and R⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶is H, and R⁷ is —OCH₃. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ isH, and R⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (III), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H,and R⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is H, Z is Formula (III), R³ is CH₃,R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is F, Z is Formula (III), R³ isCH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, andR⁷ is —OCH₃. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H,R⁶ is H, and R⁷ is —OCH₃. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is —OCH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ isF. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷is F. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H,and R⁷ is F. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ isF. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is F. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H,and R⁷ is F. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is F, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is H, R⁵ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is F,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is F, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is F, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is F, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is F, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is F, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is F,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is F, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is F, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is F, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is F, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is F, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is F, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is F, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is F, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is F, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is F, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is F, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is F,R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is F, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is F, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is F, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is F, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is F, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is F, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is F, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is F, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is F, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is F,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is F, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is F, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is F, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), one of R⁴, R⁵, and R⁷is H, and each of the remaining R⁴, R⁵, and R⁷ is halogen. In anexemplary embodiment, the compound is Formula (I), R³, R^(3a), X and Yare as described herein, Z is Formula (II), one of R⁴, R⁵, and R⁷ is H,and each of the remaining R⁴, R⁵, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), X and Y are asdescribed herein, Z is Formula (II), one of R⁴, R⁵, and R⁷ is H, andeach of the remaining R⁴, R⁵, and R⁷ is Cl. In an exemplary embodiment,the compound is Formula (I), R³, R^(3a), X and Y are as describedherein, Z is Formula (II), one of R⁴, R⁵, and R⁷ is H, one of R⁴, R⁵,and R⁷ is Cl and one of R⁴, R⁵, and R⁷ is F.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵is H, and R⁷ is F. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is H, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is F, Z isFormula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ isH, and R⁷ is F. In an exemplary embodiment, the compound is Formula (I),X and Y are as described herein, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵is H, and R⁷ is F. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is CH₃,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment,the compound is Formula (I), X and Y are as described herein, Z isFormula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is F.In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃,R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (II), R³is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H,R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ isF. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is F. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H,and R⁷ is F. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is F. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is F. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ isCl. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷is Cl. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is H, R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H,and R⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is Cl. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is H, and R⁷ is Cl. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is Cl.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ isCl. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is Cl. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H,and R⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is Cl. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is Cl. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is Cl. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is Cl.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is Cl, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is Cl,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is Cl, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is Cl, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is H, R⁵ is Cl, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is Cl, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is Cl,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is H, Z is Formula (III), R³is H, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is H, R⁶ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is Cl,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is Cl, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is Cl, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is Cl,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ is H. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is OH, Z isFormula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is Cl, and R⁷ isH.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is Cl, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is Cl, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴is Cl, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is Cl, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isCH₃, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl,R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) isH, R⁴ is Cl, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is Cl, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is H, Z is Formula (III), R³is H, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴is Cl, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷is H. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is Cl, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is Cl,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is F, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ is H. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is OH, Z isFormula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is Cl, R⁶ is H, and R⁷ isH.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ isH, and R⁷ is CH₃. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) is H,R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵is H, and R⁷ is CH₃. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (II), R³ is CH₃,R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷is CH₃. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃,R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁵ is H, and R⁷ is CH₃. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁵ is H, and R⁷ is CH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ isH, and R⁷ is CH₃. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (III), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H,and R⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I),Y is as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶is H, and R⁷ is CH₃. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (III), R³ is CH₃,R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is H, and R⁷ is CH₃. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is CH₃. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is CH₃.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ isCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵is CH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (II), R³ is CH₃,R^(3a) is CH₃, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is CH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁵ is CH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁵ is CH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ isCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (III), R³ is H,R^(3a) is H, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isH, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶is CH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (III), R³ is CH₃,R^(3a) is CH₃, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is CH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is CH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is CH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is CH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁶ is CH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is CH₃, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is CH₃, R⁵is H, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is CH₃, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) isH, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is CH₃,R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (II), R³ isCH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁵ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isCH₃, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is CH₃, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is CH₃, R⁵ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is CH₃, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is CH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is H, R^(3a) is H, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is CH₃, R⁶is H, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is OH, Z is Formula (III), R³ is H,R^(3a) is H, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is CH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) isH, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is CH₃,R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is Formula (III), R³ isCH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isCH₃, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is CH₃, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is CH₃, R⁶ is H,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is CH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is H, andR⁷ is CN. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), X and Y are as described herein, Z is Formula (II), R⁴ is H, R⁵is H, and R⁷ is CN. In an exemplary embodiment, the compound is Formula(I), R³, R^(3a), X and Y are as described herein, Z is Formula (II), R⁴is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), X and Y are as described herein, Z is Formula(II), R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ isH, and R⁷ is CN. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is F, Z is Formula (II), R³ is H,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is OH, Z isFormula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. Inan exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵is H, and R⁷ is CN. In an exemplary embodiment, the compound is Formula(I), Y is as described herein, X is H, Z is Formula (II), R³ is CH₃,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is F, Z isFormula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵is H, and R⁷ is CN. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (II), R³ is CH₃,R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷is CN. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃,R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is OH, Z is Formula (II), R³is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H,and R⁷ is CN. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁵ is H, and R⁷ is CN. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is CN. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H,R⁵ is H, and R⁷ is CN.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is H, andR⁷ is CN. In an exemplary embodiment, the compound is Formula (I), R³,R^(3a), and Y are as described herein, X is H, Z is Formula (III), R⁴ isH, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), Y is as described herein, X is F, Z is Formula(III), R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), and Y are as described herein, X isOH, Z is Formula (III), R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is CN. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is H, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (III), R³is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is CN. In an exemplary embodiment, the compound is Formula (I), X and Yare as described herein, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴is H, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷is CN. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H,R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, Z is Formula (III), R³is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, andR⁷ is CN. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is H, and R⁷ is CN. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is H, and R⁷ is CN. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is CN. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is H, andR⁷ is CN. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a)is H, R⁴ is H, R⁶ is H, and R⁷ is CN.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is H, R⁵ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),R³, R^(3a), Y is as described herein, X is H, Z is Formula (II), R⁴ isH, R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), Y is as described herein, X is F, Z is Formula(II), R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), R³, R^(3a), Y is as described herein, X is OH,Z is Formula (II), R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is H, Z is Formula (II), R³ is H, R^(3a) is H,R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is F, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is—OCH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is Formula (II), R³ is CH₃,R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is F, Z is Formula (II), R³ is CH₃, R^(3a) is H,R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is OH, Z is Formula(II), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (II), R³ isCH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁵ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H,R⁵ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is F, Z is Formula (II), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁵ is —OCH₃,and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),R³, R^(3a), Y is as described herein, X is H, Z is Formula (III), R⁴ isH, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), R³, R^(3a), Y is as described herein, X is F, Z is Formula(III), R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment,the compound is Formula (I), R³, R^(3a), Y is as described herein, X isOH, Z is Formula (III), R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is F, Z is Formula (III), R³ isCH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isOH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is Formula (III), R³ is CH₃, R^(3a) isCH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is H,R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (III), R³is CH₃, R^(3a) is CH₃, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ isH, R⁶ is —OCH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is H, Z is Formula (III), R³ is—CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is H, R⁶ is —OCH₃,and R⁷ is H. In an exemplary embodiment, the compound is Formula (I), Yis as described herein, X is OH, Z is Formula (III), R³ is —CH₂NH₂,R^(3a) is H, R⁴ is H, R⁶ is —OCH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (II), R⁴ is —CH₂NH₂, R⁵ isH, and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),X and Y are as described herein, Z is Formula (II), R³ is H, R^(3a) isH, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), Y is as described herein, X is H, Z is Formula(II), R³ is H, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is F, Z is Formula (II), R³ is H, R^(3a) is H, R⁴ is —CH₂NH₂,R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), Y is as described herein, X is OH, Z is Formula (II), R³ isH, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ isH, and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),Y is as described herein, X is H, Z is Formula (II), R³ is CH₃, R^(3a)is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment,the compound is Formula (I), Y is as described herein, X is F, Z isFormula (II), R³ is CH₃, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), Y is asdescribed herein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is H, R⁴is —CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(II), R³ is CH₃, R^(3a) is CH₃, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is—CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (II), R³is CH₃, R^(3a) is CH₃, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is CH₃, R^(3a) is CH₃, R⁴ is—CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, Z is Formula (II), R³is —CH₂NH₂, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—CH₂NH₂, R⁵ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (II), R³is —CH₂NH₂, R^(3a) is H, R⁴ is —CH₂NH₂, R⁵ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (II), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—CH₂NH₂, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), R³, R^(3a), Xand Y are as described herein, Z is Formula (III), R⁴ is —CH₂NH₂, R⁶ isH, and R⁷ is H. In an exemplary embodiment, the compound is Formula (I),R³, R^(3a), Y is as described herein, X is H, Z is Formula (III), R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), R³, R^(3a), Y is as described herein, X is F, Z isFormula (III), R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), R³, R^(3a), Y is as describedherein, X is OH, Z is Formula (III), R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ isH. In an exemplary embodiment, the compound is Formula (I), X and Y areas described herein, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is H, Z is Formula (III), R³is H, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplaryembodiment, the compound is Formula (I), Y is as described herein, X isF, Z is Formula (III), R³ is H, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), Y isas described herein, X is OH, Z is Formula (III), R³ is H, R^(3a) is H,R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, thecompound is Formula (I), X and Y are as described herein, Z is Formula(III), R³ is CH₃, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. Inan exemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (III), R³is CH₃, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is H, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, Z is Formula (III), R³is CH₃, R^(3a) is CH₃, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (III), R³is CH₃, R^(3a) is CH₃, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is CH₃, R^(3a) is CH₃, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, Z is Formula (III), R³is —CH₂NH₂, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is H, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H. In an exemplary embodiment, the compoundis Formula (I), Y is as described herein, X is F, Z is Formula (III), R³is —CH₂NH₂, R^(3a) is H, R⁴ is —CH₂NH₂, R⁶ is H, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), Y is as describedherein, X is OH, Z is Formula (III), R³ is —CH₂NH₂, R^(3a) is H, R⁴ is—CH₂NH₂, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁴, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R³, R^(3a), R⁴, R⁷, Xand Y are as described herein, and said Z is according to Formula (IV).In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is according to Formula (IV), R³ is H, R^(3a) is H,R⁴ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is according to Formula(IV), R³ is H, R^(3a) is H, R⁴ is H, and R⁷ is Cl or CH₃. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is according to Formula (IV), R³ is H, R^(3a) is H,R⁴ is F or Cl or CH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R³, R^(3a), R⁵, andR⁷, X and Y are as described herein, and said Z is according to Formula(V). In an exemplary embodiment, the compound is Formula (I), X and Yare as described herein, Z is according to Formula (V), R³ is H, R^(3a)is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is according to Formula(V), R³ is H, R^(3a) is H, R⁵ is H, and R⁷ is Cl or CH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is according to Formula (V), R³ is H, R^(3a) is H, R⁵ is F orCl or CH₃, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁴, R⁵, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. Inan exemplary embodiment, the compound is Formula (I), R³, R^(3a), R⁴,R⁵, and R⁷, X and Y are as described herein, and said Z is according toFormula (VI). In an exemplary embodiment, the compound is Formula (I), Xand Y are as described herein, Z is according to Formula (VI), R³ is H,R^(3a) is H, R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment,the compound is Formula (I), X and Y are as described herein, Z isaccording to Formula (VI), R³ is H, R^(3a) is H, R⁴ is H, R⁵ is H, andR⁷ is Cl or CH₃. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is according to Formula (VI), R³is H, R^(3a) is H, R⁴ is H, R⁵ is F or Cl or CH₃, and R⁷ is H. In anexemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is according to Formula (VI), R³ is H, R^(3a) is H,R⁴ is F or Cl or CH₃, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R^(3a), R⁴, R⁶, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. Inan exemplary embodiment, the compound is Formula (I), R³, R^(3a), R⁴,R⁶, and R⁷, X and Y are as described herein, and said Z is according toFormula (VII). In an exemplary embodiment, the compound is Formula (I),X and Y are as described herein, Z is according to Formula (VII), R³ isH, R^(3a) is H, R⁴ is H, R⁶ is H, and R⁷ is F. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is according to Formula (VII), R³ is H, R^(3a) is H, R⁴ is H,R⁶ is H, and R⁷ is Cl or CH₃. In an exemplary embodiment, the compoundis Formula (I), X and Y are as described herein, Z is according toFormula (VII), R³ is H, R^(3a) is H, R⁴ is H, R⁶ is F or Cl or CH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is according to Formula (VII), R³ is H,R^(3a) is H, R⁴ is F or Cl or CH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R³, R⁴, R⁵, and R⁷, Xand Y are as described herein, and said Z is according to Formula(VIII). In an exemplary embodiment, the compound is Formula (I), X and Yare as described herein, Z is according to Formula (VIII), R³ is H, R⁴is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is according to Formula(VIII), R³ is H, R⁴ is H, R⁵ is H, and R⁷ is Cl or CH₃. In an exemplaryembodiment, the compound is Formula (I), X and Y are as describedherein, Z is according to Formula (VIII), R³ is H, R⁴ is H, R⁵ is F orCl or CH₃, and R⁷ is H. In an exemplary embodiment, the compound isFormula (I), X and Y are as described herein, Z is according to Formula(VIII), R³ is H, R⁴ is F or Cl or CH₃, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³, R⁴, R⁶, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R³, R⁴, R⁶, and R⁷, Xand Y are as described herein, and said Z is according to Formula (IX).In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, Z is according to Formula (IX), R³ is H, R⁴ is H, R⁶is H, and R⁷ is F. In an exemplary embodiment, the compound is Formula(I), X and Y are as described herein, Z is according to Formula (IX), R³is H, R⁴ is H, R⁶ is H, and R⁷ is Cl or CH₃. In an exemplary embodiment,the compound is Formula (I), X and Y are as described herein, Z isaccording to Formula (IX), R³ is H, R⁴ is H, R⁶ is F or Cl or CH₃, andR⁷ is H. In an exemplary embodiment, the compound is Formula (I), X andY are as described herein, Z is according to Formula (IX), R³ is H, R⁴is F or Cl or CH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R¹, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R¹, R⁴, R⁵, and R⁷, Xand Y are as described herein, and said Z is according to Formula (X).In an exemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁵,and R⁷ are as described herein, Z is according to Formula (X), and R¹ isH. In an exemplary embodiment, the compound is Formula (I), X, Y, R⁴,R⁵, and R⁷ are as described herein, Z is according to Formula (X), andR¹ is an ester. In an exemplary embodiment, the compound is Formula (I),X, Y, R⁴, R⁵, and R⁷ are as described herein, Z is according to Formula(X), and R¹ is a ketone. In an exemplary embodiment, the compound isFormula (I), X, Y, R⁴, R⁵, and R⁷ are as described herein, Z isaccording to Formula (X), and R¹ is —C(O)OC(CH₃)₃. In an exemplaryembodiment, the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are asdescribed herein, Z is according to Formula (X), and R¹ is —S(O)₂R^(1a),wherein R^(1a) is substituted or unsubstituted C₁-C₆ alkyl. In anexemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷are as described herein, Z is according to Formula (X), and R¹ is—S(O)₂CH₃. In an exemplary embodiment, the compound is Formula (I), X,Y, R⁴, R⁵, and R⁷ are as described herein, Z is according to Formula(X), and R¹ is —CH₃. In an exemplary embodiment, the compound is Formula(I), X, Y, R⁴, R⁵, and R⁷ are as described herein, Z is according toFormula (X), and R¹ is —CH₂CH₃. In an exemplary embodiment, the compoundis Formula (I), X, Y, R⁴, R⁵, and R⁷ are as described herein, Z isaccording to Formula (X), and R¹ is C₃-C₆ alkyl. In an exemplaryembodiment, the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are asdescribed herein, Z is according to Formula (X), and R¹ is —C(O)R^(1a),wherein R^(1a) is substituted or unsubstituted C₁-C₆ alkyl. In anexemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷are as described herein, Z is according to Formula (X), and R¹ is—C(O)CH₃. In an exemplary embodiment, the compound is Formula (I), X, Y,R⁴, R⁵, and R⁷ are as described herein, Z is according to Formula (X),and R¹ is —C(O)OR^(1a), wherein R^(1a) is substituted or unsubstitutedC₁-C₆ alkyl. In an exemplary embodiment, the compound is Formula (I), X,Y, R⁴, R⁵, and R⁷ are as described herein, Z is according to Formula(X), and R¹ is —C(O)OCH₃. In an exemplary embodiment, the compound isFormula (I), R¹, X and Y are as described herein, Z is according toFormula (X), R⁴ is H, R⁵ is H, and R⁷ is F. In an exemplary embodiment,the compound is Formula (I), R¹, X and Y are as described herein, Z isaccording to Formula (X), R⁴ is H, R⁵ is H, and R⁷ is Cl or CH₃. In anexemplary embodiment, the compound is Formula (I), R¹, X and Y are asdescribed herein, Z is according to Formula (X), R⁴ is H, R⁵ is F or Clor CH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), R¹, X and Y are as described herein, Z is according to Formula (X),R⁴ is F or Cl or CH₃, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R¹, R⁴, R⁶, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R¹, R⁴, R⁶, and R⁷, Xand Y are as described herein, and said Z is according to Formula (XI).In an exemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁶,and R⁷ are as described herein, Z is according to Formula (XI), and R¹is H. In an exemplary embodiment, the compound is Formula (I), X, Y, R⁴,R⁶, and R⁷ are as described herein, Z is according to Formula (XI), andR¹ is an ester. In an exemplary embodiment, the compound is Formula (I),X, Y, R⁴, R⁶, and R⁷ are as described herein, Z is according to Formula(XI), and R¹ is a ketone. In an exemplary embodiment, the compound isFormula (I), X, Y, R⁴, R⁶, and R⁷ are as described herein, Z isaccording to Formula (XI), and R¹ is —C(O)OC(CH₃)₃. In an exemplaryembodiment, the compound is Formula (I), X, Y, R⁴, R⁶, and R⁷ are asdescribed herein, Z is according to Formula (XI), and R¹ is—S(O)₂R^(1a), wherein R^(1a) is substituted or unsubstituted C₁-C₆alkyl. In an exemplary embodiment, the compound is Formula (I), X, Y,R⁴, R⁶, and R⁷ are as described herein, Z is according to Formula (XI),and R¹ is —S(O)₂CH₃. In an exemplary embodiment, the compound is Formula(I), X, Y, R⁴, R⁶, and R⁷ are as described herein, Z is according toFormula (XI), and R¹ is —CH₃. In an exemplary embodiment, the compoundis Formula (I), X, Y, R⁴, R⁶, and R⁷ are as described herein, Z isaccording to Formula (XI), and R¹ is —CH₂CH₃. In an exemplaryembodiment, the compound is Formula (I), X, Y, R⁴, R⁶, and R⁷ are asdescribed herein, Z is according to Formula (XI), and R¹ is C₃-C₆ alkyl.In an exemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁶,and R⁷ are as described herein, Z is according to Formula (XI), and R¹is —C(O)R^(1a), wherein R^(1a) is substituted or unsubstituted C₁-C₆alkyl. In an exemplary embodiment, the compound is Formula (I), X, Y,R⁴, R⁶, and R⁷ are as described herein, Z is according to Formula (XI),and R¹ is —C(O)CH₃. In an exemplary embodiment, the compound is Formula(I), X, Y, R⁴, R⁶, and R⁷ are as described herein, Z is according toFormula (XI), and R¹ is —C(O)OR^(1a), wherein R^(1a) is substituted orunsubstituted C₁-C₆ alkyl. In an exemplary embodiment, the compound isFormula (I), X, Y, R⁴, R⁶, and R⁷ are as described herein, Z isaccording to Formula (XI), and R¹ is —C(O)OCH₃. In an exemplaryembodiment, the compound is Formula (I), R¹, X and Y are as describedherein, Z is according to Formula (XI), R⁴ is H, R⁶ is H, and R⁷ is F.In an exemplary embodiment, R¹, X and Y are as described herein, Z isaccording to Formula (XI), R⁴ is H, R⁶ is H, and R⁷ is Cl or CH₃. In anexemplary embodiment, the compound is Formula (I), R¹, X and Y are asdescribed herein, Z is according to Formula (XI), R⁴ is H, R⁶ is F or Clor CH₃, and R⁷ is H. In an exemplary embodiment, the compound is Formula(I), R¹, X and Y are as described herein, Z is according to Formula(XI), R⁴ is F or Cl or CH₃, R⁶ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R³ and R^(3a) are each independently selected from the groupconsisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R³, R^(3a), X and Yare as described herein, and said Z is according to Formula (XII) or(XIII). In an exemplary embodiment, the compound is Formula (I), X and Yare as described herein, and said Z is according to Formula (XII) or(XIII), wherein R³ is H, and R^(3a) is H.

In an exemplary embodiment, the compound is Formula (I), X and Y are asdescribed herein, and said Z is

wherein R¹, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. In anexemplary embodiment, the compound is Formula (I), R¹, R⁴, R⁵, R⁷, X andY are as described herein, and said Z is according to Formula (XIV). Inan exemplary embodiment, the compound is Formula (I), X, Y, R⁴, R⁵, andR⁷ are as described herein, and said Z is according to Formula (XIV),and R¹ is H. In an exemplary embodiment, the compound is Formula (I), X,Y, R⁴, R⁵, and R⁷ are as described herein, and said Z is according toFormula (XIV), and R¹ is an ester. the compound is Formula (I), X, Y,R⁴, R⁵, and R⁷ are as described herein, and said Z is according toFormula (XIV), and R¹ is a ketone. the compound is Formula (I), X, Y,R⁴, R⁵, and R⁷ are as described herein, and said Z is according toFormula (XIV), and R¹ is —C(O)OC(CH₃)₃. the compound is Formula (I), X,Y, R⁴, R⁵, and R⁷ are as described herein, and said Z is according toFormula (XIV), and R¹ is —S(O)₂R^(1a), wherein R^(1a) is substituted orunsubstituted C₁-C₆ alkyl. the compound is Formula (I), X, Y, R⁴, R⁵,and R⁷ are as described herein, and said Z is according to Formula(XIV), and R¹ is —S(O)₂CH₃. the compound is Formula (I), X, Y, R⁴, R⁵,and R⁷ are as described herein, and said Z is according to Formula(XIV), and R¹ is —CH₃. the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷are as described herein, and said Z is according to Formula (XIV), andR¹ is —CH₂CH₃. the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are asdescribed herein, and said Z is according to Formula (XIV), and R¹ isC₃-C₆ alkyl. the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are asdescribed herein, and said Z is according to Formula (XIV), and R¹ is—C(O)R^(1a)wherein R^(1a) is substituted or unsubstituted C₁-C₆ alkyl.the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are as describedherein, and said Z is according to Formula (XIV), and R¹ is —C(O)CH₃.the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are as describedherein, and said Z is according to Formula (XIV), and R¹ is —C(O)OR^(1a)wherein R^(1a) is substituted or unsubstituted C₁-C₆ alkyl. the compoundis Formula (I), X, Y, R⁴, R⁵, and R⁷ are as described herein, and said Zis according to Formula (XIV), and R¹ is —C(O)OCH₃. the compound isFormula (I), X, Y, R⁴, R⁵, and R⁷ are as described herein, and said Z isaccording to Formula (XIV), and R⁴ is H, R⁵ is H, and R⁷ is F. thecompound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are as described herein,and said Z is according to Formula (XIV), and R⁴ is H, R⁵ is H, and R⁷is Cl or CH₃. the compound is Formula (I), X, Y, R⁴, R⁵, and R⁷ are asdescribed herein, and said Z is according to Formula (XIV), and R⁴ is H,R⁵ is F or Cl or CH₃, and R⁷ is H. the compound is Formula (I), X, Y,R⁴, R⁵, and R⁷ are as described herein, and said Z is according toFormula (XIV), and R⁴ is F or Cl or CH₃, R⁵ is H, and R⁷ is H.

In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is H, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z is as described herein, X is H, and Y is—O—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is H, and Y is —S—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is H, and Y is—NH—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is H, and Y is substituted alkylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isH, and Y is unsubstituted alkylene. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is H, and Y issubstituted heteroalkylene. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is H, and Y is unsubstitutedheteroalkylene. In an exemplary embodiment, the compound is Formula (I),Z is as described herein, X is H, and Y is methylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isH, and Y is ethylene. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is H, and Y is propylene. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is H, and Y is substituted heteroalkylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isH, and Y is unsubstituted heteroalkylene. In an exemplary embodiment,the compound is Formula (I), Z is as described herein, X is H, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Z isas described herein, X is H, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isH, and Y is *—NHCH₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is H, and Y is *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is H, and Y is *—C(O)NH—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is H, and Y is*—CH₂NHCH₂— or 1-piperazinyl or *—S(O)CH₂— or *—S(O)₂— or *—S(O)₂CH₂—.In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is H, and Y is 1-piperazinyl. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isH, and Y is *—S(O)CH₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is H, and Y is *—S(O)₂—. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is H, and Y is *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is H, and Y is*—NHC(O)OCH₂—. In this paragraph, * represents the point of attachmentto Z.

In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is F, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z is as described herein, X is F, and Y is—O—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is F, and Y is —S—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is F, and Y is—NH—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is F, and Y is substituted alkylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isF, and Y is unsubstituted alkylene. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is F, and Y issubstituted heteroalkylene. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is F, and Y is unsubstitutedheteroalkylene. In an exemplary embodiment, the compound is Formula (I),Z is as described herein, X is F, and Y is methylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isF, and Y is ethylene. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is F, and Y is propylene. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is F, and Y is substituted heteroalkylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isF, and Y is unsubstituted heteroalkylene. In an exemplary embodiment,the compound is Formula (I), Z is as described herein, X is F, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Z isas described herein, X is F, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isF, and Y is *—NHCH₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is F, and Y is *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is F, and Y is *—C(O)NH—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is F, and Y is*—CH₂NHCH₂— or 1-piperazinyl or *—S(O)CH₂— or *—S(O)₂— or *—S(O)₂CH₂—.In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is F, and Y is 1-piperazinyl. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isF, and Y is *—S(O)CH₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is F, and Y is *—S(O)₂—. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is F, and Y is *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is F, and Y is*—NHC(O)OCH₂—. In this paragraph, * represents the point of attachmentto Z.

In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is OH, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z is as described herein, X is OH, and Y is—O—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is OH, and Y is —S—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is OH, and Y is—NH—. In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is OH, and Y is substituted alkylene. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is OH, and Y is unsubstituted alkylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isOH, and Y is substituted heteroalkylene. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is OH, and Y isunsubstituted heteroalkylene. In an exemplary embodiment, the compoundis Formula (I), Z is as described herein, X is OH, and Y is methylene.In an exemplary embodiment, the compound is Formula (I), Z is asdescribed herein, X is OH, and Y is ethylene. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isOH, and Y is propylene. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is OH, and Y is substitutedheteroalkylene. In an exemplary embodiment, the compound is Formula (I),Z is as described herein, X is OH, and Y is unsubstitutedheteroalkylene. In an exemplary embodiment, the compound is Formula (I),Z is as described herein, X is OH, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isOH, and Y is *—SCH₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is OH, and Y is *—NHCH₂—. In anexemplary embodiment, the compound is Formula (I), Z is as describedherein, X is OH, and Y is *—CH₂NH—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is OH, and Y is*—C(O)NH—. In an exemplary embodiment, the compound is Formula (I), Z isas described herein, X is OH, and Y is *—CH₂NHCH₂— or 1-piperazinyl or*—S(O)CH₂— or *—S(O)₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is as described herein, X is OH, and Y is1-piperazinyl. In an exemplary embodiment, the compound is Formula (I),Z is as described herein, X is OH, and Y is *—S(O)CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is as described herein, X isOH, and Y is *—S(O)₂—. In an exemplary embodiment, the compound isFormula (I), Z is as described herein, X is OH, and Y is *—S(O)₂CH₂—. Inan exemplary embodiment, the compound is Formula (I), Z is as describedherein, X is OH, and Y is *—NHC(O)OCH₂—. In this paragraph, * representsthe point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is H, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is a bond.In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is H, and Y is a bond.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is H, and Y is a bond. In an exemplary embodiment, the compoundis Formula (I), Z is substituted or unsubstituted heterocycloalkyl,wherein said heterocycloalkyl has two rings, and one of the two ringscomprises an endocyclic boron, X is H, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborole, X is H, and Y is a bond. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is H, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborininol, X is H, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is H, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzodiazaborininol, X is H, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedoxaborole, X is H, and Y is a bond. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is H, and Y is a bond.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is H, and Y is —NH—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is H, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is H, and Y is —NH—. In an exemplary embodiment, the compoundis Formula (I), Z is substituted or unsubstituted heterocycloalkyl,wherein said heterocycloalkyl has two rings, and one of the two ringscomprises an endocyclic boron, X is H, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborole, X is H, and Y is —NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is H, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborininol, X is H, and Y is —NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is H, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzodiazaborininol, X is H, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstituted oxaborole, Xis H, and Y is —NH—. In an exemplary embodiment, the compound is Formula(I), Z substituted or unsubstituted dihydrobenzoazaborinine, X is H, andY is —NH—.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is H, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is H, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is H, and Y is *—OCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is H, and Y is *—OCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is H, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is H, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is H, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is H, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is H, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is H, and Y is *—OCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is H, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is H, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is H, and Y is *—SCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is H, and Y is *—SCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is H, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is H, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is H, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is H, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is H, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is H, and Y is *—SCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is *—NHCH₂— or *—CH₂NH—. Inan exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heteroaryl, wherein said heteroaryl has onering, and said ring comprises an endocyclic boron, X is H, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has two rings, and one of the two rings comprises anendocyclic boron, X is H, and Y is *—NHCH₂— or *—CH₂NH—. In an exemplaryembodiment, the compound is Formula (I), Z is substituted orunsubstituted heterocycloalkyl, wherein said heterocycloalkyl comprisesan endocyclic boron, X is H, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is H, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heterocycloalkyl, whereinsaid heterocycloalkyl has two rings, and one of the two rings comprisesan endocyclic boron, X is H, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborole, X is H, and Y is *—NHCH₂— or *—CH₂NH—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is H, and Y is *—NHCH₂— or *—CH₂NH—.In an exemplary embodiment, the compound is Formula (I), Z substitutedor unsubstituted benzoxaborininol, X is H, and Y is *—NHCH₂— or*—CH₂NH—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxazaborininol, X is H, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted benzodiazaborininol, X is H,and Y is *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compoundis Formula (I), Z substituted or unsubstituted oxaborole, X is H, and Yis *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted dihydrobenzoazaborinine, Xis H, and Y is *—NHCH₂— or *—CH₂NH—. In this paragraph, * represents thepoint of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is H, and Y is *—C(O)NH— or *—S(O)CH₂—or *—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I),and Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has one ring, and said ring comprises an endocyclic boron, Xis H, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl comprises an endocyclicboron, X is H, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is H, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is H, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted benzoxaborole, Xis H, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is H, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborininol, X is H, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is H, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzodiazaborininol, X is H, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted oxaborole, X isH, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is H, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In this paragraph, * represents the point of attachment toZ.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is F, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is a bond.In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is F, and Y is a bond.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is F, and Y is a bond. In an exemplary embodiment, the compoundis Formula (I), Z is substituted or unsubstituted heterocycloalkyl,wherein said heterocycloalkyl has two rings, and one of the two ringscomprises an endocyclic boron, X is F, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborole, X is F, and Y is a bond. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is F, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborininol, X is F, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is F, and Y is a bond. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzodiazaborininol, X is F, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedoxaborole, X is F, and Y is a bond. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is F, and Y is a bond.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is F, and Y is —NH—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is F, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is F, and Y is —NH—. In an exemplary embodiment, the compoundis Formula (I), Z is substituted or unsubstituted heterocycloalkyl,wherein said heterocycloalkyl has two rings, and one of the two ringscomprises an endocyclic boron, X is F, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborole, X is F, and Y is —NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is F, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborininol, X is F, and Y is —NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is F, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzodiazaborininol, X is F, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstituted oxaborole, Xis F, and Y is —NH—. In an exemplary embodiment, the compound is Formula(I), Z substituted or unsubstituted dihydrobenzoazaborinine, X is F, andY is —NH—.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is F, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is F, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is F, and Y is *—OCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is F, and Y is *—OCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is F, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is F, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is F, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is F, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is F, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is F, and Y is *—OCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is F, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is F, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is F, and Y is *—SCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is F, and Y is *—SCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is F, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is F, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is F, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is F, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is F, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is F, and Y is *—SCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is *—NHCH₂— or *—CH₂NH—. Inan exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heteroaryl, wherein said heteroaryl has onering, and said ring comprises an endocyclic boron, X is F, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has two rings, and one of the two rings comprises anendocyclic boron, X is F, and Y is *—NHCH₂— or *—CH₂NH—. In an exemplaryembodiment, the compound is Formula (I), Z is substituted orunsubstituted heterocycloalkyl, wherein said heterocycloalkyl comprisesan endocyclic boron, X is F, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is F, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heterocycloalkyl, whereinsaid heterocycloalkyl has two rings, and one of the two rings comprisesan endocyclic boron, X is F, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborole, X is F, and Y is *—NHCH₂— or *—CH₂NH—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is F, and Y is *—NHCH₂— or *—CH₂NH—.In an exemplary embodiment, the compound is Formula (I), Z substitutedor unsubstituted benzoxaborininol, X is F, and Y is *—NHCH₂— or*—CH₂NH—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxazaborininol, X is F, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted benzodiazaborininol, X is F,and Y is *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compoundis Formula (I), Z substituted or unsubstituted oxaborole, X is F, and Yis *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted dihydrobenzoazaborinine, Xis F, and Y is *—NHCH₂— or *—CH₂NH—. In this paragraph, * represents thepoint of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is F, and Y is *—C(O)NH— or *—S(O)CH₂—or *—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I),and Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has one ring, and said ring comprises an endocyclic boron, Xis F, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl comprises an endocyclicboron, X is F, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is F, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is F, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted benzoxaborole, Xis F, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is F, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborininol, X is F, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is F, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzodiazaborininol, X is F, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted oxaborole, X isF, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is F, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In this paragraph, * represents the point of attachment toZ.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is OH, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is abond. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is OH, and Y is abond. In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is OH, and Y is a bond. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is abond. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is OH, and Y is a bond. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is OH, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is OH, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is OH, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is OH, and Y is a bond. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is OH, and Y is a bond. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is OH, and Y is a bond.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), and Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has one ring, and saidring comprises an endocyclic boron, X is OH, and Y is —NH—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is OH, and Y is —NH—.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is OH, and Y is —NH—. In an exemplary embodiment, the compoundis Formula (I), Z is substituted or unsubstituted heterocycloalkyl,wherein said heterocycloalkyl has two rings, and one of the two ringscomprises an endocyclic boron, X is OH, and Y is —NH—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborole, X is OH, and Y is —NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is OH, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxaborininol, X is OH, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is OH, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstitutedbenzodiazaborininol, X is OH, and Y is —NH—. In an exemplary embodiment,the compound is Formula (I), Z substituted or unsubstituted oxaborole, Xis OH, and Y is —NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted dihydrobenzoazaborinine, Xis OH, and Y is —NH—.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heteroaryl, wherein said heteroaryl has one ring, andsaid ring comprises an endocyclic boron, X is OH, and Y is *—OCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z is substitutedor unsubstituted heteroaryl, wherein said heteroaryl has two rings, andone of the two rings comprises an endocyclic boron, X is OH, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is OH, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is OH, and Y is *—OCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is*—OCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is OH, and Y is *—OCH₂—.In an exemplary embodiment, the compound is Formula (I), Z substitutedor unsubstituted pyridinyloxaborole, X is OH, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is OH, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is OH, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is OH, and Y is *—OCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is OH, and Y is *—OCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is OH, and Y is *—OCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heteroaryl, wherein said heteroaryl has one ring, andsaid ring comprises an endocyclic boron, X is OH, and Y is *—SCH₂—. Inan exemplary embodiment, the compound is Formula (I), Z is substitutedor unsubstituted heteroaryl, wherein said heteroaryl has two rings, andone of the two rings comprises an endocyclic boron, X is OH, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl comprises an endocyclic boron, X is OH, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), and Zis substituted or unsubstituted heterocycloalkyl, wherein saidheterocycloalkyl has one ring, and said ring comprises an endocyclicboron, X is OH, and Y is *—SCH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is*—SCH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborole, X is OH, and Y is *—SCH₂—.In an exemplary embodiment, the compound is Formula (I), Z substitutedor unsubstituted pyridinyloxaborole, X is OH, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborininol, X is OH, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxazaborininol, X is OH, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzodiazaborininol, X is OH, and Y is *—SCH₂—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted oxaborole, X is OH, and Y is *—SCH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is OH, and Y is *—SCH₂—. In this paragraph, *represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is *—NHCH₂— or *—CH₂NH—.In an exemplary embodiment, the compound is Formula (I), and Z issubstituted or unsubstituted heteroaryl, wherein said heteroaryl has onering, and said ring comprises an endocyclic boron, X is OH, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has two rings, and one of the two rings comprises anendocyclic boron, X is OH, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z is substituted orunsubstituted heterocycloalkyl, wherein said heterocycloalkyl comprisesan endocyclic boron, X is OH, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is OH, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z is substituted or unsubstituted heterocycloalkyl, whereinsaid heterocycloalkyl has two rings, and one of the two rings comprisesan endocyclic boron, X is OH, and Y is *—NHCH₂— or *—CH₂NH—. In anexemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted benzoxaborole, X is OH, and Y is *—NHCH₂— or *—CH₂NH—. Inan exemplary embodiment, the compound is Formula (I), Z substituted orunsubstituted pyridinyloxaborole, X is OH, and Y is *—NHCH₂— or*—CH₂NH—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborininol, X is OH, and Y is*—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compound isFormula (I), Z substituted or unsubstituted benzoxazaborininol, X is OH,and Y is *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, the compoundis Formula (I), Z substituted or unsubstituted benzodiazaborininol, X isOH, and Y is *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted oxaborole, X isOH, and Y is *—NHCH₂— or *—CH₂NH—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is OH, and Y is *—NHCH₂— or *—CH₂NH—. In thisparagraph, * represents the point of attachment to Z.

In an exemplary embodiment, the compound is Formula (I), Z issubstituted or unsubstituted heteroaryl, wherein said heteroarylcomprises an endocyclic boron, X is OH, and Y is *—C(O)NH— or *—S(O)CH₂—or *—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I),and Z is substituted or unsubstituted heteroaryl, wherein saidheteroaryl has one ring, and said ring comprises an endocyclic boron, Xis OH, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z is substituted orunsubstituted heteroaryl, wherein said heteroaryl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl comprises an endocyclicboron, X is OH, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In anexemplary embodiment, the compound is Formula (I), and Z is substitutedor unsubstituted heterocycloalkyl, wherein said heterocycloalkyl has onering, and said ring comprises an endocyclic boron, X is OH, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z is substituted or unsubstitutedheterocycloalkyl, wherein said heterocycloalkyl has two rings, and oneof the two rings comprises an endocyclic boron, X is OH, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted benzoxaborole, Xis OH, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstitutedpyridinyloxaborole, X is OH, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzoxaborininol, X is OH, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstitutedbenzoxazaborininol, X is OH, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In an exemplary embodiment, the compound is Formula (I), Zsubstituted or unsubstituted benzodiazaborininol, X is OH, and Y is*—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplary embodiment, thecompound is Formula (I), Z substituted or unsubstituted oxaborole, X isOH, and Y is *—C(O)NH— or *—S(O)CH₂— or *—S(O)₂CH₂—. In an exemplaryembodiment, the compound is Formula (I), Z substituted or unsubstituteddihydrobenzoazaborinine, X is OH, and Y is *—C(O)NH— or *—S(O)CH₂— or*—S(O)₂CH₂—. In this paragraph, * represents the point of attachment toZ.

The compounds of the invention can form a hydrate with water, solvateswith alcohols such as methanol, ethanol, propanol, and the like; adductswith amino compounds, such as ammonia, methylamine, ethylamine, and thelike; adducts with acids, such as formic acid, acetic acid and the like;complexes with ethanolamine, quinoline, amino acids, and the like.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In an exemplary embodiment, the salt is a pharmaceuticallyacceptable salt. In an exemplary embodiment, the invention provides acompound described herein, or a hydrate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a salt of a compound describedherein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

In an exemplary embodiment, alkyl is linear alkyl. In another exemplaryembodiment, alkyl is branched alkyl.

In an exemplary embodiment, heteroalkyl is linear heteroalkyl. Inanother exemplary embodiment, heteroalkyl is branched heteroalkyl.

III. b) Combinations Comprising Additional Therapeutically Active Agents

The compounds of the invention may also be used in combination with atleast one other therapeutically active agent. The invention thusprovides, in a further aspect, a combination comprising a compound ofthe invention together with at least one other therapeutically activeagent, or a salt, prodrug, hydrate or solvate thereof. In an exemplaryembodiment, the compound of the invention is a compound describedherein, or a salt thereof. In an exemplary embodiment, the additionaltherapeutically active agent is a compound of the invention. In anexemplary embodiment, the additional therapeutic agent includes a boronatom. In an exemplary embodiment, the additional therapeutic agent doesnot contain a boron atom. In an exemplary embodiment, the additionaltherapeutic agent is a compound described in section III a).

When a compound of the invention is used in combination with a secondtherapeutic agent active against the same disease state, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian.

The individual components of such combinations may be administeredeither simultaneously or sequentially in a unit dosage form. The unitdosage form may be a single or multiple unit dosage forms. In anexemplary embodiment, the invention provides a combination in a singleunit dosage form. An example of a single unit dosage form is a capsulewherein both the compound of the invention and the additionaltherapeutic agent are contained within the same capsule. In an exemplaryembodiment, the invention provides a combination in a two unit dosageform. An example of a two unit dosage form is a first capsule whichcontains the compound of the invention and a second capsule whichcontains the additional therapeutic agent. Thus the term ‘single unit’or ‘two unit’ or ‘multiple unit’ refers to the object which the animal(for example, a human) ingests, not to the interior components of theobject. Appropriate doses of known therapeutic agents will be readilyappreciated by those skilled in the art.

The combinations referred to herein may conveniently be presented foruse in the form of a pharmaceutical formulation. Thus, an exemplaryembodiment of the invention is a pharmaceutical formulation comprisinga) a compound of the invention; b) an additional therapeutic agent andc) a pharmaceutically acceptable excipient. In an exemplary embodiment,the pharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.In an exemplary embodiment, the pharmaceutical formulation is a singleunit dosage form which includes a compound of the invention; anantibacterial and a pharmaceutically acceptable excipient. In anexemplary embodiment, the pharmaceutical formulation is a single unitdosage form which includes a compound of the invention; an antibacterialand at least one pharmaceutically acceptable excipient. In an exemplaryembodiment, the pharmaceutical formulation is a two unit dosage form. Inan exemplary embodiment, the pharmaceutical formulation is a two unitdosage form comprising a first unit dosage form and a second unit dosageform, wherein the first unit dosage form includes a) a compound of theinvention and b) a first pharmaceutically acceptable excipient; and thesecond unit dosage form includes c) an additional therapeutic agent andd) a second pharmaceutically acceptable excipient. In an exemplaryembodiment, the pharmaceutical formulation is a two unit dosage formcomprising a first unit dosage form and a second unit dosage form,wherein the first unit dosage form includes a) a compound of theinvention and b) a first pharmaceutically acceptable excipient; and thesecond unit dosage form includes c) an antibacterial and d) a secondpharmaceutically acceptable excipient.

III. c) Preparation of Compounds of the Invention

Compounds of the invention can be prepared using commercially availablestarting materials, known intermediates, or by using the syntheticmethods published in references described and incorporated by referenceherein, such as U.S. patent application Ser. No. 12/142,692 and U.S.Pat. Pubs. US20060234981, US20070155699 and US20070293457.

The following general procedures were used as indicated in generatingthe examples and can be applied, using the knowledge of one of skill inthe art, to other appropriate compounds to obtain additional analogues.Benzoxaborole, benzoxaborininol, and benzodiazaborininol are shown belowfor exemplary purposes. The procedures are adaptable to any of the boronring systems described herein.

General Procedure 1:

A general method of creating a modified pleuromutilin is provided below:

A general method of attaching a modified pleuromutilin to a ring systemcontaining at least one endocyclic boron is provided below.

General Procedure 2:

A general method of creating a modified pleuromutilin is provided below:

A general method of attaching a modified pleuromutilin to a ring systemcontaining at least one endocyclic boron is provided below.

General Procedure 3:

A general method of creating a modified pleuromutilin is provided below:

A general method of attaching a modified pleuromutilin to a ring systemcontaining at least one endocyclic boron is provided below:

General Procedure 4: Synthesis of Pleuromutilins with C2 Modified withOH

A general method of attaching a C2-modified pleuromutilin to a ringsystem containing at least one endocyclic boron is provided below:

General Procedure 5: Synthesis of Pleuromutilins with C2 Modified with F

A general method of attaching a C2-modified pleuromutilin to a ringsystem containing at least one endocyclic boron is provided below:

IV. Methods

In another aspect, the compounds of the invention and/or combinations ofthe invention can be utilized to inhibit protein synthesis in abacteria. In another aspect, the compounds of the invention and/orcombinations of the invention exhibit potency against microorganisms,such as bacteria, and worms, and therefore have the potential to killand/or inhibit the growth of them. In another aspect, the compounds ofthe invention and/or combinations of the invention exhibit potencyagainst microorganisms, such as bacteria, and worms, and therefore havethe potential to achieve therapeutic efficacy in infections by thesemicroorganisms and/or worms in the animals described herein. In anexemplary embodiment, the bacteria is Gram-positive. In anotherexemplary embodiment, the bacteria is a symbiont with another organism.In another exemplary embodiment, the bacteria is a symbiont with a worm.In another exemplary embodiment, the bacteria is a symbiont with anarthropod.

IV. a) Inhibiting Microorganism Growth or Killing Microorganisms

The compounds of the invention and/or combinations of the inventionexhibit potency against microorganisms, such as bacteria, and thereforehave the potential to treat, and/or prevent a microorganism infection,or kill and/or inhibit the growth of microorganisms.

In a further aspect, the invention provides a method of inhibiting thegrowth of and/or killing a bacteria, the method comprising contactingthe bacteria with a compound of the invention, or a pharmaceuticallyacceptable salt or a hydrate or a solvate thereof, thereby inhibitingthe growth of and/or killing the bacteria. In an exemplary embodiment,the bacteria is contacting with a therapeutically effective amount ofthe compound of the invention. In an exemplary embodiment, the bacteriais contacting with a prophylactically effective amount of the compoundof the invention.

In a further aspect, the invention provides a method of treating and/orpreventing a microorganism infection, or a method of killing and/orinhibiting the growth of a microorganism, said method comprisingcontacting said microorganism with an effective amount of a compound ofthe invention, thereby killing and/or inhibiting the growth of themicroorganism. In a further aspect, the invention provides a method oftreating and/or preventing a microorganism infection, or a method ofkilling and/or inhibiting the growth of a microorganism, said methodcomprising contacting said microorganism with an effective amount of acombination of the invention, thereby killing and/or inhibiting thegrowth of the microorganism.

In a further aspect, the invention provides a method of treating and/orpreventing a microorganism infection, or a method of killing and/orinhibiting the growth of a microorganism, said method comprisingcontacting said microorganism with a compound of the invention, therebykilling and/or inhibiting the growth of the microorganism. In a furtheraspect, the invention provides a method of treating and/or preventing amicroorganism infection, or a method of killing and/or inhibiting thegrowth of a microorganism, said method comprising contacting saidmicroorganism with an effective amount of a compound of the invention,thereby killing and/or inhibiting the growth of the microorganism. In afurther aspect, the invention provides a method of treating and/orpreventing a microorganism infection, or a method of killing and/orinhibiting the growth of a microorganism, said method comprising:contacting said microorganism with an effective amount of a combinationof the invention, thereby killing and/or inhibiting the growth of themicroorganism.

In a further aspect, the invention provides a method of treating abacterial infection comprising administering to an animal suffering fromthe infection an effective amount of a compound of the invention or acombination of the invention, or a pharmaceutically acceptable saltthereof, thereby treating the bacterial infection. In an exemplaryembodiment, the invention provides a method of treating a bacterialinfection comprising administering to an animal suffering from theinfection an effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, and an effective amount of anantibacterial, or a pharmaceutically acceptable salt thereof, therebytreating the bacterial infection.

In a further aspect, the invention provides a method of preventing abacterial infection comprising administering to an animal a prophylacticamount of a compound of the invention or a combination of the invention,or a pharmaceutically acceptable salt thereof, thereby treating thebacterial infection. In an exemplary embodiment, the invention providesa method of preventing a bacterial infection comprising administering toan animal a prophylactic amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

In an exemplary embodiment, the microorganism is a bacteria. In anexemplary embodiment, the compound or combination is described herein,or a salt, prodrug, hydrate or solvate thereof, or a combinationthereof. In an exemplary embodiment, the invention provides a compoundor combination described herein, or a salt, hydrate or solvate thereof.In an exemplary embodiment, the invention provides a compound orcombination described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a compound or combination describedherein, or a salt thereof. In another exemplary embodiment, the compoundor combination of the invention is a compound or combination describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound or compound of the combination isdescribed by a formula listed herein, or a pharmaceutically acceptablesalt thereof. In an exemplary embodiment, the compound is part of acombination described herein. In an exemplary embodiment, the compoundis part of a pharmaceutical formulation described herein. In anotherexemplary embodiment, the contacting occurs under conditions whichpermit entry of the compound into the organism. Such conditions areknown to one skilled in the art and are described herein.

In another aspect, the microorganism is inside, and/or on the surface ofan animal. In an exemplary embodiment, the animal is selected from thegroup consisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human.

In an exemplary embodiment, the microorganism infection is treated andor prevented, and/or the microorganism is killed or its growth isinhibited, through oral administration of the compound of the inventionand/or the combination of the invention. In an exemplary embodiment, themicroorganism infection is treated and or prevented, and/or themicroorganism is killed or its growth is inhibited through intravenousadministration of the compound of the invention and/or the combinationof the invention.

In an exemplary embodiment, the microorganism is a bacteria. In anexemplary embodiment, an infection is caused by and/or associated with amicroorganism, particularly a bacteria. In an exemplary embodiment, thebacteria is a Gram-positive bacteria. In another exemplary embodiment,the Gram-positive bacteria is selected from the group consisting ofStaphylococcus species, Streptococcus species, Bacillus species,Mycobacterium species, Corynebacterium species (Propionibacteriumspecies), Clostridium species, Actinomyces species, Enterococcusspecies, Streptomyces species, Listeria species. In another exemplaryembodiment, the Gram-positive bacteria is selected from the groupconsisting of Propionibacterium acnes, Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcushaemolyticus, Streptococcus pyogenes, Streptococcus agalactiae,Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium,Bacillus anthracis, Mycobacterium avium-intracellulare, Mycobacteriumtuberculosis, Corynebacterium diphtheria, Clostridium perfringens,Clostridium botulinum, Clostridium tetani, Clostridium difficile, andListeria monocytogenes. In another exemplary embodiment, theGram-positive bacteria is selected from the group consisting ofStaphylococcus aureus, Staphylococcus epidermidis, Streptococcuspneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Clostridium difficile and Propionibacter acnes. In an exemplaryembodiment, the bacteria is a coagulase positive Staphylococci. In anexemplary embodiment, the bacteria is a coagulase negativeStaphylococci. In another exemplary embodiment, the bacteria isStaphylococcus aureus. In another exemplary embodiment, the bacteria ismethicillin-resistant Staphylococcus aureus. In another exemplaryembodiment, the bacteria is health care-associated methicillin-resistantStaphylococcus aureus. In another exemplary embodiment, the bacteria iscommunity-associated methicillin-resistant Staphylococcus aureus. Inanother exemplary embodiment, the bacteria is Staphylococcusepidermidis. In another exemplary embodiment, the bacteria isStreptococcus pneumoniae. In another exemplary embodiment, the bacteriais Streptococcus pyogenes. In another exemplary embodiment, the bacteriais Streptococcus agalactiae. In another exemplary embodiment, thebacteria is a beta-hemolytic Streptococci. In another exemplaryembodiment, the bacteria is a beta-hemolytic Streptococcus pyogenes. Inanother exemplary embodiment, the bacteria is a beta-hemolyticStreptococcus agalactiae. In another exemplary embodiment, the bacteriais a group A Streptococci. In another exemplary embodiment, the bacteriais a group A Streptococcus pyogenes. In another exemplary embodiment,the bacteria is a group B Streptococci. In another exemplary embodiment,the bacteria is a group B Streptococcus agalactiae. In another exemplaryembodiment, the bacteria is Enterococcus faecalis. In another exemplaryembodiment, the bacteria is Enterococcus faecium.

In an exemplary embodiment, the microorganism is a bacteria, and thebacteria is a Gram-negative bacteria. In an exemplary embodiment, thebacteria is a Haemophilus species. In an exemplary embodiment, thebacteria is Haemophilus influenzae. In an exemplary embodiment, thebacteria is a Moraxella species. In an exemplary embodiment, thebacteria is Moraxella catarrhalis.

In an exemplary embodiment, the compounds of the invention exhibitpotency against bacteria which are associated with worms. In anexemplary embodiment, the compounds of the invention exhibit potencyagainst bacteria which live inside of worms. In an exemplary embodiment,the compounds of the invention exhibit potency against bacteria whichare essential for worm survival. In an exemplary embodiment, thecompounds of the invention exhibit potency against bacteria which are asymbiont for a worm. In an exemplary embodiment, the invention providesa method of killing and/or inhibiting the growth of a bacteria which isassociated with a worm, comprising contacting the bacteria with aneffective amount of the compound of the invention, thereby killingand/or inhibiting the growth of the bacteria. In an exemplaryembodiment, the bacteria is of the Wolbachia genus. In an exemplaryembodiment, the bacteria is Wolbachia pipientis.

IV. b) Inhibiting Worm Growth or Killing Worms

The compounds of the present invention exhibit potency against certainworms as a consequence of their ability to kill the endosymbioticbacteria of the Wolbachia genus, and therefore have the potential tokill and/or inhibit the growth of such worms. The invention thereforeprovides a method of killing a worm, comprising contacting the worm withan effective amount of the compound of the invention, thereby killingthe worm. The invention provides a method of inhibiting the growth of aworm, comprising contacting the worm with an effective amount of thecompound of the invention, thereby inhibiting the growth of the worm. Inan exemplary embodiment, the worm is female. In an exemplary embodiment,the worm is male. In an exemplary embodiment, the worm is ahermaphrotide. In an exemplary embodiment, the worm is an egg. In anexemplary embodiment, the worm is an unfertilized egg. In an exemplaryembodiment, the worm is fertilized egg. In an exemplary embodiment, theworm is a larvae. In an exemplary embodiment, the worm is mature. In anexemplary embodiment, the worm is fully mature. In an exemplaryembodiment, the worm is contacted with the compound of the inventioninside an animal. In an exemplary embodiment, the worm is contacted withthe compound of the invention outside of an animal.

In an exemplary embodiment, the worm is a parasitic worm. In anexemplary embodiment, the worm is a helminth. In an exemplaryembodiment, the worm is a nematode. In an exemplary embodiment, thenematode is a filarid. In an exemplary embodiment, the nematode is amember of Filarioidea. In an exemplary embodiment, the nematode is amember of Onchocercinae. In an exemplary embodiment, the nematode is amember of Dirofilariinae. In an exemplary embodiment, the nematode is afilarid. In an exemplary embodiment, the nematode is a filarial worm. Inan exemplary embodiment, the nematode is a member of the genusWuchereria. In an exemplary embodiment, the nematode is Wuchereriabancrofti. In an exemplary embodiment, the nematode is a member of thegenus Brugia. In an exemplary embodiment, the nematode is Brugia malayi.In an exemplary embodiment, the nematode is Brugia timori. In anexemplary embodiment, the Brugia is a microfilariae. In an exemplaryembodiment, the Brugia is a larvae. In an exemplary embodiment, theBrugia is mature. In an exemplary embodiment, the Brugia is contacted bythe compound of the invention in the skin of the animal. In an exemplaryembodiment, the Brugia is contacted by the compound of the invention inthe lymphatic system of the animal. In an exemplary embodiment, theBrugia is contacted by the compound of the invention in the blood of theanimal. In an exemplary embodiment, the Brugia is contacted by thecompound of the invention in the muscle of the animal. In an exemplaryembodiment, the Brugia is contacted by the compound of the invention inthe salivary gland of the animal.

In an exemplary embodiment, the nematode is a member of the genusMansonella. In an exemplary embodiment, the nematode is selected fromthe group consisting of Mansonella streptocerca, Mansonella perstans,and Mansonella ozzardi. In an exemplary embodiment, the nematode is amember of the genus Onchocerca. In an exemplary embodiment, the nematodeis Onchocerca volvulus. In an exemplary embodiment, the nematode isOnchocerca ochengi.

In an exemplary embodiment, the nematode is a heartworm. In an exemplaryembodiment, the nematode is a member of the genus Dirofilaria. In anexemplary embodiment, the nematode is Dirofilaria immitis. In anexemplary embodiment, the nematode is Dirofilaria tenuis or Dirofilariarepens.

IV. c) Diseases

The compounds of the invention and/or combinations of the inventionexhibit potency against microorganisms, such as bacteria, and thereforehave the potential to achieve therapeutic efficacy in the animalsdescribed herein. The compounds of the invention and/or combinations ofthe invention exhibit potency against worms, and therefore have thepotential to achieve therapeutic efficacy in the animals describedherein.

In another aspect, the invention provides a method of treating and/orpreventing a disease. In an exemplary embodiment, the method includesadministering to the animal a therapeutically and/or prophylacticallyeffective amount of a compound of the invention, sufficient to treatand/or prevent the disease. In an exemplary embodiment, the methodincludes administering to the animal a therapeutically and/orprophylactically effective amount of a combination of the invention,sufficient to treat and/or prevent the disease. In an exemplaryembodiment, the animal being administered the compound is not otherwisein need of treatment with a compound of the invention.

In an exemplary embodiment, the compound of the invention or thecombination of the invention can be used in human or veterinary medicaltherapy, particularly in the treatment or prophylaxis ofbacterial-associated disease. In an exemplary embodiment, the compoundof the invention or the combination of the invention can be used inhuman or veterinary medical therapy, particularly in the treatment of aGram-positive bacterial-associated disease. In an exemplary embodiment,the compound of the invention or the combination of the invention can beused in human or veterinary medical therapy, particularly in theprophylaxis of a Gram-positive bacterial-associated disease. In anexemplary embodiment, the compound of the invention or the combinationof the invention can be used in human or veterinary medical therapy,particularly in the treatment of a Wolbachia-associated disease. In anexemplary embodiment, the compound of the invention or the combinationof the invention can be used in human or veterinary medical therapy,particularly in the prophylaxis of a Wolbachia-associated disease. Inanother exemplary embodiment, the disease is pneumonia. In anotherexemplary embodiment, the disease is hospital-acquired pneumonia. Inanother exemplary embodiment, the disease is hospital-associatedpneumonia. In another exemplary embodiment, the disease iscommunity-acquired pneumonia. In another exemplary embodiment, thedisease is a acute bacterial skin and skin-structure infection (ABSSSI).In another exemplary embodiment, the disease is bacteremia. In anotherexemplary embodiment, the disease is endocarditis. In another exemplaryembodiment, the disease is osteomyelitis. In an exemplary embodiment,the disease is associated with a Staphylococcus species. In anotherexemplary embodiment, the disease is selected from the group consistingof pneumonia, gastroenteritis, toxic shock syndrome, community acquiredpneumonia (CAP), meningitis, septic arthritis, urinary tract infection,bacteremia, endocarditis, osteomylitis, skin and skin-structureinfection. In an exemplary embodiment, the disease is associated with aStreptococcus species. In another exemplary embodiment, the disease isselected from the group consisting of strep throat, skin infections,necrotizing fasciitis, toxic shock syndrome, pneumonia, otitis media andsinusitis. In an exemplary embodiment, the disease is associated with anActinomyces species. In another exemplary embodiment, the disease isactinomycosis. In an exemplary embodiment, the disease is associatedwith a Norcardia species. In another exemplary embodiment, the diseaseis pneumonia. In an exemplary embodiment, the disease is associated witha Corynebacterium species. In another exemplary embodiment, the diseaseis diptheria. In an exemplary embodiment, the disease is associated witha Listeria species. In another exemplary embodiment, the disease ismeningitis. In an exemplary embodiment, the disease is associated with aBacillus species. In another exemplary embodiment, the disease isanthrax or food poisoning. In an exemplary embodiment, the disease isassociated with a Clostridium species. In another exemplary embodiment,the disease is selected from the group consisting of botulism, tetanus,gas gangrene and diarrhea. In an exemplary embodiment, the disease isassociated with a Mycobacterium species. In another exemplaryembodiment, the disease is tuberculosis or leprosy. In an exemplaryembodiment, the disease is associated with a Listeria species. In anexemplary embodiment, the disease is associated with a Wolbachiaspecies. In an exemplary embodiment, the disease is associated withWolbachia pipientis. In an exemplary embodiment, the disease is selectedfrom the group consisting of candidiasis, aspergillosis,coccidioidomycosis, cryptococcosis, histoplasmosis, blastomycosis,paracoccidioidomycosis, zygomycosis, phaeohyphomycosis andrhinosporidiosis.

In an exemplary embodiment, the compound of the invention can be used inhuman medical therapy, particularly in the treatment of worm-associateddisease. In an exemplary embodiment, the compound of the invention canbe used in human medical therapy, particularly in the prophylaxis ofworm-associated disease. In an exemplary embodiment, the compound of theinvention can be used in veterinary medical therapy, particularly in thetreatment of worm-associated disease. In an exemplary embodiment, thecompound of the invention can be used in veterinary medical therapy,particularly in the prophylaxis of worm-associated disease. In anexemplary embodiment, the compound of the invention can be used in humanmedical therapy, particularly in the treatment of helminth-associateddisease. In an exemplary embodiment, the compound of the invention canbe used in human medical therapy, particularly in the prophylaxis ofhelminth-associated disease. In an exemplary embodiment, the compound ofthe invention can be used in veterinary medical therapy, particularly inthe treatment of helminth-associated disease. In an exemplaryembodiment, the compound of the invention can be used in veterinarymedical therapy, particularly in the prophylaxis of helminth-associateddisease. In an exemplary embodiment, the disease is associated with aworm. In an exemplary embodiment, the disease is caused by a worm. In anexemplary embodiment, the disease is associated with a worm describedherein. In an exemplary embodiment, the disease is associated with anematode. In an exemplary embodiment, the disease is associated with anematode described herein. In an exemplary embodiment, the nematode isWuchereria bancrofti. In an exemplary embodiment, the nematode is Brugiamalayi. In an exemplary embodiment, the nematode is Brugia timori. In anexemplary embodiment, the nematode is Dirofilaria immitis. In anexemplary embodiment, the disease is a member selected fromenterobiasis, filariasis, and onchocerciasis. In an exemplaryembodiment, the disease is lymphatic filariasis. In an exemplaryembodiment, the disease is bancroftian filariasis. In an exemplaryembodiment, the disease is lymphadenitis. In an exemplary embodiment,the disease is lymphangitis. In an exemplary embodiment, the disease islymphedema. In an exemplary embodiment, the disease is subcutaneousfilariasis. In an exemplary embodiment, the disease is serious cavityfilariasis. In an exemplary embodiment, the disease is elephantiasis. Inan exemplary embodiment, the disease is elephantiasis tropica. In anexemplary embodiment, the disease is onchocerciasis.

In another exemplary embodiment, the animal is selected from the groupconsisting of human, cattle, deer, reindeer, goat, honey bee, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel,yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl,pigeon, swan, and turkey. In another exemplary embodiment, the animal isa human. In another exemplary embodiment, the animal is selected fromthe group consisting of a human, cattle, goat, pig, sheep, horse, cow,bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey. Inanother exemplary embodiment, the disease is a systemic disease. Inanother exemplary embodiment, the disease is a topical disease.

In an exemplary embodiment, the disease is treated through oraladministration of a compound of the invention and/or a combination ofthe invention. In an exemplary embodiment, the disease is treatedthrough intravenous administration of a compound of the invention and/ora combination of the invention. In an exemplary embodiment, the diseaseis treated through intramuscular administration of a compound of theinvention and/or a combination of the invention. In an exemplaryembodiment, the disease is treated through topical administration of acompound of the invention and/or a combination of the invention.

In an exemplary embodiment, for any of the methods described herein, acompound of the invention, a combination of the invention, a compounddescribed herein or a pharmaceutically acceptable salt thereof, orcombination described herein, and/or a pharmaceutical formulationdescribed herein can be used.

V. Pharmaceutical Formulations

In another aspect, the invention is a pharmaceutical formulation whichincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound of the invention. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound according to a formula described herein. In anotheraspect, the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a compound described herein, or a salt,prodrug, hydrate or solvate thereof. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a compound described herein, or a salt, hydrate orsolvate thereof. In another aspect, the pharmaceutical formulationincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound described herein, or a salt, hydrate or solvate thereof. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a salt of a compounddescribed herein. In an exemplary embodiment, the salt is apharmaceutically acceptable salt. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a prodrug of a compound described herein. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a compound described herein. In an exemplaryembodiment, the pharmaceutical formulation is a unit dosage form. In anexemplary embodiment, the pharmaceutical formulation is a single unitdosage form.

Information regarding excipients of use in the formulations of theinvention can be found in Remington: The Science and Practice ofPharmacy, 21st Ed., Pharmaceutical Press (2011) which is incorporatedherein by reference.

Exemplary embodiments are summarized herein below.

In an exemplary embodiment, the invention provides a compound, or a saltor a hydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein X is H or F or OH; Y is selected from the group consisting of abond, —O—, —S—, —NH—, substituted or unsubstituted alkylene, andsubstituted or unsubstituted heteroalkylene; and Z is a substituted orunsubstituted heterocyclic ring or ring system containing at least oneendocyclic boron.

In an exemplary embodiment, according to the above paragraph, thecompound, or a salt or a hydrate or a solvate thereof, wherein said Y is*—OCH₂— or *—SCH₂— or *—NHCH₂— or *—CH₂NH— or *—C(O)NH—, wherein *represents the point of attachment to said Z.

In an exemplary embodiment, according to any of the above paragraphs,for the compound, or a salt or a hydrate or a solvate thereof, whereinsaid Z is selected from the group consisting of substituted orunsubstituted benzoxaborole, substituted or unsubstitutedpyridinyloxaborole, substituted or unsubstituted benzoxaborininol,substituted or unsubstituted benzoxazaborininol, substituted orunsubstituted benzodiazaborininol, substituted or unsubstitutedoxaborole, and substituted or unsubstituted dihydrobenzoazaborinine.

In an exemplary embodiment, according to any of the above paragraphs,for the compound, or a salt or a hydrate or a solvate thereof, whereinsaid Z is

wherein R³, R^(3a), R⁴, R⁵, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹, whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, which is(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, which is(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, which is(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, wherein saidZ is

wherein R³, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹, wherein R¹⁰ andR¹¹ are each independently selected from the group consisting of H,halogen, cyano, nitro, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, which is(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, wherein saidZ is

wherein R¹, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.

In an exemplary embodiment, according to any of the above paragraphs,the compound, or a salt or a hydrate or a solvate thereof, which ismethyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate.

In an exemplary embodiment, the invention provides a combinationcomprising: the compound of a preceding claim, or a pharmaceuticallyacceptable salt thereof, together with at least one othertherapeutically active agent.

In an exemplary embodiment, according to the above combinationparagraph, wherein the other therapeutically active agent is ananti-bacterial agent.

In an exemplary embodiment, the invention provides a pharmaceuticalformulation comprising: a) the compound of a preceding claim, or apharmaceutically acceptable salt or a hydrate or a solvate thereof; andb) a pharmaceutically acceptable excipient.

In an exemplary embodiment, according to the above pharmaceuticalformulation paragraph, the pharmaceutical formulation is an oralformulation or an intravenous formulation.

In an exemplary embodiment, according to any of the above paragraphs,the salt of the compound according to any of the above paragraphs is apharmaceutically acceptable salt.

In an exemplary embodiment, the invention is a method of inhibitingprotein synthesis in a bacteria, the method comprising contacting thebacteria with the compound in any of the above paragraphs, or apharmaceutically acceptable salt or a hydrate or a solvate thereof,thereby inhibiting protein synthesis in the bacteria.

In an exemplary embodiment, the invention is a method of inhibiting thegrowth of and/or killing a bacteria, the method comprising contactingthe bacteria with the compound in any of the above paragraphs, or apharmaceutically acceptable salt or a hydrate or a solvate thereof,thereby inhibiting the growth of and/or killing the bacteria.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the bacteria is Gram-positive.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the bacteria is Staphylococcus aureus orStreptococcus pneumoniae.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the bacteria is methicillin-resistant Staphylococcusaureus.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the bacteria is of the Wolbachia genus.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the bacteria is Wolbachia pipientis.

In an exemplary embodiment, the invention is a method of treating adisease in an animal in need of the treatment, the method comprisingadministering to the animal a therapeutically effective amount of thecompound in any of the above paragraphs, or a pharmaceuticallyacceptable salt or a hydrate or a solvate thereof, thereby treating thedisease.

In an exemplary embodiment, according to the above method paragraph,wherein the disease is associated with a Gram-positive bacteria.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the disease is pneumonia.

In an exemplary embodiment, according to any of the above methodparagraphs, wherein the disease is onchocerciasis.

In an exemplary embodiment, according to any of the above methodparagraphs, the animal is a human.

In an exemplary embodiment, according to any of the above methodparagraphs, there is a proviso that the animal is not otherwise in needof treatment with a compound of the invention.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

EXAMPLES

Proton NMR are recorded on Varian AS 300 spectrometer and chemicalshifts are reported as δ (ppm) down field from tetramethylsilane. Massspectra are determined on Micromass Quattro II.

Example 1 1.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

TosCl (19.1 g, 0.1 mol) in 1, 2-dichloroethane (100 mL) was slowly addedto a mixture of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-hydroxyacetate (35.4 g, 0.1 mol), triethylamine (12.0 g, 0.1 mol) andpyridine (1 mL) in 1, 2-dichloroethane (100 mL). The mixture was stirredat 10-15° C. for 20 hrs, washed with water (3×100 mL), then concentratedto dryness. Purification was achieved by recrystallization fromDCM/Petroleum ether (1:100) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate as a white solid (45.0 g, yield 90.0%). ¹H NMR(DMSO-d₆, 400 MHz) δ 7.80 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H),6.05 (dd, J=17.8, 11.2 Hz, 1H), 5.53 (d, J=8.4 Hz, 1H), 5.09-4.96 (m,2H), 4.81-4.59 (m, 2H), 3.40 (d, J=5.6 Hz, 1H), 2.41 (s, 2H), 2.39 (br.s., 1H), 2.24-1.95 (m, 5H), 1.75-1.41 (m, 4H), 1.30 (s, 4H), 1.27-1.18(m, 4H), 1.03 (s, 3H), 0.99-0.92 (m, 2H), 0.81 (d, J=7.2 Hz, 3H), 0.50(d, J=7.2 Hz, 3H).

Tos-pleuromutilin (1.8 g, 3.3 mmol), benzo[c][1,2]oxaborole-1,6(3H)-diol (0.5 g, 3.3 mmol) and K₂CO₃ (0.7 g, 5.0 mmol) in20 mL of DMF was heated to 50° C. overnight. Main peak was product inLCMS. Water was added and the mixture was adjust pH<4 with 2N HCl. Thesolid was filtered and the crude product was purified by Pre-HPLC(column: Luna C18 250×30 mm, 10 μm; liquid phase: [A-TFA/H₂O=0.1% v/v;B-ACN] B %: 35%-65%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (1.0 g, yield 57.0%). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.30 (d, J=8.4Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.4, 2.4 Hz, 1H) 6.10 (dd,J=17.6, 11.2 Hz, 1H), 5.59 (d, J=8.4 Hz, 1H), 5.11-4.97 (m, 2H), 4.91(s, 2H), 4.76-4.63 (m, 2H), 3.41 (d, J=5.6 Hz, 1H), 2.40 (br. s., 1H),2.26-1.99 (m, 4H), 1.72-1.43 (m, 4H), 1.38 (d, J=13.2 Hz, 1H), 1.34 (s,3H), 1.29-1.15 (m, 4H), 1.03 (s, 3H), 1.01 (br. s., 1H), 0.81 (d, J=6.8Hz, 3H), 0.63 (d, J=6.8 Hz, 3H).

2.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of Tos-pleuromutilin (51.5 g, 96.7 mmol, 1.0 eq.) in CH₃CN(600.0 mL) was added NaI (87.0 g, 580.1 mmol, 6.0 eq.). The mixture wasstirred at 90° C. for 16 hours. HPLC indicated the reaction wascompleted. The reaction mixture was concentrated under reduced pressureto remove CH₃CN. The residue was diluted with H₂O (500 mL) and extractedwith DCM (500 mL×3). The combined organic layers were concentrated underreduced pressure to give a residue. The residue was washed withpetroleum ether (200 mL).(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-iodoacetate (40.0 g, 81.9 mmol, 84.7% yield) was obtained as a yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 6.11 (dd, J=11.2, 17.9 Hz, 1H), 5.52(d, J=7.9 Hz, 1H), 5.13-5.01 (m, 2H), 4.55 (d, J=5.7 Hz, 1H), 3.82-3.75(m, 1H), 3.73-3.66 (m, 1H), 3.43 (t, J=5.3 Hz, 1H), 2.45-2.39 (m, 1H),2.25-2.00 (m, 4H), 1.72-1.57 (m, 2H), 1.53-1.21 (m, 9H), 1.11-0.97 (m,4H), 0.83 (d, J=6.6 Hz, 3H), 0.64 (d, J=7.1 Hz, 3H).

To a solution of 2,3-difluorophenol (300.0 g, 2.3 mol, 1.0 eq) in DCM(1.5 L) was added MOM-Cl (278.9 g, 3.5 mol, 1.5 eq) and DIEA (597.1 g,4.6 mol, 2.0 eq). The mixture was stirred at 0° C. for 2 hours. TLCindicated that STM was consumed. The reaction mixture was quenched byaddition of H₂O (1500 mL) at 0° C., and then was adjusted to pH=6. Thecombined organic layers were washed with saturation NH₄Cl (500 mL×3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. 1,2-difluoro-3-(methoxymethoxy)benzene (400.0 g, 2.3mol, 99.4% yield) was obtained as yellow oil which was used into thenext step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ7.03-6.93 (m, 1H), 6.89-6.78 (m, 1H), 5.28-5.20 (m, 2H), 3.58-3.50 (m,3H)

To a solution of 1,2-difluoro-3-(methoxymethoxy)benzene (100.0 g, 574.3mmol, 1.0 eq.) in THF (1.5 L) was added BuLi (2.5 M, 298.6 mL, 1.3 eq.).The mixture was stirred at −78° C. for 7 hours. Then ethylformate (85.1g, 1150 mmol, 2.0 eq.) was added and the mixture was stirred for another1 hour. TLC indicated that STM was consumed completely. The reactionmixture was quenched by addition of H₂O (1000 mL) at 0° C., and then wasextracted with EtOAc (800 mL×3). The combined organic layers were washedwith brine 1000 mL, dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The3,4-difluoro-2-(methoxymethoxy)benzaldehyde (492.0 g, crude) as a yellowoil was used into the next step without further purification. ¹H NMR(CDCl₃, 400 MHz) δ 10.40-10.29 (m, 1H), 7.73-7.57 (m, 1H), 7.11-6.98 (m,1H), 5.33 (s, 2H), 3.63-3.58 (m, 3H).

To a solution of 3,4-difluoro-2-(methoxymethoxy)benzaldehyde (256.0 g,1.27 mol, 1.0 eq.) in DMF (1.5 L) was added Cs₂CO₃ (618.9 g, 1.90 mol,1.5 eq.) and phenylmethanol (136.9 g, 1.3 mol, 1.0 eq.). The mixture wasstirred at 70° C. for 10 hours. TLC indicated that STM was consumedcompletely. The reaction mixture was quenched by addition of H₂O (1000mL) at 0° C., and then diluted with EtOAc (1200 mL) and extracted withEtOAc (1200 mL×2). The combined organic layers were washed with H₂O(1000 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue.4-(benzyloxy)-3-fluoro-2-(methoxymethoxy)benzaldehyde (400.0 g, crude)as a yellow oil, which was used into the next step without furtherpurification.

To a solution of 4-(benzyloxy)-3-fluoro-2-(methoxymethoxy)benzaldehyde(760.0 g, 2.6 mol, 1.0 eq.) in CH₃OH (600.0 mL) was added aq. HCl (2 M,200.0 mL). The mixture was stirred at 40° C. for 4 hours. TLC indicatedthat STM was consumed completely. The reaction was quenched by additionof H₂O (300 mL) and the mixture was concentrated under reduced pressureto remove CH₃OH. The residue was diluted with DCM 500 mL and extractedwith DCM 1000 mL (500 mL×2). The combined organic layers were washedwith brine (500 mL×3), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=20:1 to 5:1).4-(benzyloxy)-3-fluoro-2-hydroxybenzaldehyde (225.0 g, 913.8 mmol, 34.9%yield) was obtained as a black-brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ10.97 (s, 1H), 10.06 (s, 1H), 7.34-7.52 (m, 6H), 6.90-6.98 (m, 1H), 5.28(s, 2H).

To a solution of 4-(benzyloxy)-3-fluoro-2-hydroxybenzaldehyde (117.0 g,475.2 mmol, 1.0 eq.), pyridine (75.2 g, 950.3 mmol, 2.0 eq.) and DMAP(5.8 g, 47.5 mmol, 0.1 eq.) in DCM (1.5 L) was added Tf₂O (201.1 g,712.8 mmol, 1.5 eq.) dropwise. The mixture was stirred at 0° C. for 2hours. HPLC indicated that STM was consumed completely. The reactionmixture was quenched by addition of H₂O (1000 mL), and then extractedwith DCM (1000 mL×2). The combined organic layers were washed with brine(500 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=20:1 to 2:1).3-(benzyloxy)-2-fluoro-6-formylphenyl trifluoromethanesulfonate (150.0g, 396.5 mmol, 83.5% yield) was obtained as a yellow oil. ¹H NMR (CDCl₃,400 MHz) δ 10.08 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.49-7.36 (m, 5H),7.19-7.13 (m, 1H), 5.28 (s, 2H).

To a solution of 3-(benzyloxy)-2-fluoro-6-formylphenyltrifluoromethanesulfonate (52.0 g, 137.5 mmol, 1.00 eq.), KOAc (40.5 g,412.4 mmol, 3.0 eq.) and Pin₂B₂ (104.7 g, 412.4 mmol, 3.0 eq.) indioxane (1.0 L) was added Pd (dppf) Cl₂ (2.0 g, 2.75 mmol, 0.02 eq.).The mixture was stirred at 70° C. for 16 hours. HPLC indicated that STMwas consumed completely. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=50:1 to 5:1).4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(37.0 g, 103.9 mmol, 75.6% yield) was obtained as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.81 (d, J=3.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H),7.54-7.33 (m, 7H), 5.31 (s, 2H), 1.39-1.28 (m, 12H).

To a solution of4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(20.0 g, 56.2 mmol, 1.00 eq) in THF (50.0 mL) was added NaBH₄ (3.2 g,84.2 mmol, 1.5 eq). The mixture was stirred at 0° C. for 1 hour. TLCindicated that STM was consumed completely. The reaction mixture wasquenched by addition H₂O 100 mL at 0° C., and then adjusted pH=5,removed the THF and the desired product was dissolved out, filtered andconcentrated under reduced pressure to give a residue.6-(benzyloxy)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (43.0 g, 166.6mmol, 98.9% yield) was obtained as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.31-7.48 (m, 5H), 7.17 (t, J=7.78 Hz, 1H), 7.01 (d, J=8.03 Hz,1H), 5.18 (s, 2H), 5.04 (s, 2H), 4.89 (s, 1H).

To a solution of 6-(benzyloxy)-7-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol(15.0 g, 58.1 mmol, 1.0 eq) in EtOAc (400.0 mL) was added Pd/C (2.0 g).The mixture was stirred at 25° C. for 2 hours under H₂ atmosphere (50Psi). TLC indicated that STM was consumed completely. The reactionmixture was filtered and concentrated under reduced pressure to give aresidue. 7-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (7.0 g, 41.7 mmol,71.7% yield) was obtained as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ9.59 (s, 1H), 9.14 (s, 1H), 7.05-7.12 (m, 1H), 6.97-7.03 (m, 1H), 4.88(s, 2H). MS (ESI): mass calcd. for C₇H₆BFO₃ 168.04, m/z found 167.1[M−H]⁻. HPLC: 92.5% (220 nm), 94.4% (254 nm).

To a solution of 7-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (5.0 g,29.77 mmol, 1.0 eq) and Iodo-pleuromutilin (18.9 g, 38.71 mmol, 1.3 eq)in DMSO (60.00 mL) was added Na₂CO₃ (9.5 g, 89.32 mmol, 3.0 eq). Themixture was stirred at 35° C. for 14 hours under N₂ atmosphere. HPLCindicated that STM was consumed completely. The reaction mixture wasquenched by addition H₂O (200 mL) at 0° C., and then was adjusted topH=7, solid was dissolved out and then filtered to give crude product.Combined four batches together, and the crude product was purified byprep-HPLC (column: Phenomenex luna C18 250×50 mm x 10 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 35%-65%, 20 min]), then removed theCH₃CN, resulting aqueous phase was extracted by DCM (1500 mL×3). Thecombined organic layers were concentrated under reduced pressure to givethe product as a light yellow solid. This product was dissolved in DCM,then MTBE and petroleum ether was added until the viscidity wasappeared, filtered and the filtrate was concentrated under reducedpressure to give the product as a white solid.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(15.0 g, 28.2 mmol, 24% yield, 99.0% purity) was obtained as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.26 (br. s., 1H), 7.25-7.17 (m, 1H),7.09 (d, J=7.9 Hz, 1H), 6.11 (dd, J=11.2, 17.9 Hz, 1H), 5.60 (d, J=7.9Hz, 1H), 5.10-4.98 (m, 2H), 4.92 (s, 2H), 4.86-4.74 (m, 2H), 4.52 (br.s., 1H), 3.41 (br. s., 1H), 2.41 (br. s., 1H), 2.25-2.01 (m, 4H),1.70-1.57 (m, 2H), 1.48-1.20 (m, 8H), 1.15-0.91 (m, 4H), 0.82 (d, J=6.6Hz, 3H), 0.62 (d, J=7.1 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₈BFO₇528.27, m/z found 527.3 [M−H]⁻. HPLC: 99.0% (220 nm), 100.0% (254 nm).

3.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

1,2-difluoro-4-nitrobenzene (7.1 g, 44.6 mmol), PMBOH (6.2 g, 44.6 mmol)and potassium hydroxide (3.8 g, 67.0 mmol) in 50 mL acetonitrile werestirred at room temperature overnight. Water was added to the mixture,the mixture was filtered, washed with water and dried to give2-fluoro-1-((4-methoxybenzyl)oxy)-4-nitrobenzene (11.4 g, yield 92.0%).¹H NMR (CDCl₃, 400 MHz) δ 7.96-8.08 (m, 2H), 7.37 (d, J=8.8 Hz, 2H),7.05-7.15 (m, 1H), 6.90-6.99 (m, 2H), 5.19 (s, 2H), 3.83 (s, 3H).

A mixture of 2-fluoro-1-((4-methoxybenzyl)oxy)-4-nitrobenzene (45 g, 162mmol), iron powder (27 g, 487 mmol) and ammonium chloride (26 g, 487.0mmol) in 300 mL ethanol and 50 mL water was stirred at reflux for 2hours. The mixture was filtered and washed with ethanol and the filtratewas evaporated, to the residue was added brine (200 mL) and extractedwith ethyl acetate (200 mL×3), the combined organic layers wereconcentrated to give 3-fluoro-4-((4-methoxybenzyl)oxy)aniline (29.0 g,yield 72.5%). ¹H NMR (CDCl₃, 400 MHz) δ 7.40-7.31 (m, 2H), 6.93-6.87 (m,2H), 6.81 (t, J=8.8 Hz, 1H), 6.46 (dd, J=12.8, 2.4 Hz, 1H), 6.33 (ddd,J=8.4, 2.8, 1.3 Hz, 1H), 4.96 (s, 2H), 3.82 (s, 3H), 3.51 (br. s., 2H).

NBS (14.4 g, 81.0 mmol) was added in portions to a solution of3-fluoro-4-((4-methoxybenzyl)oxy)aniline (20 g, 81 mmol) in 500 mL ofDCM at −15° C., five minutes later, new spot formed and STM consumed.Water was added to the mixture and the aqueous layer was treated withDCM, the crude product was purified by silica column to give2-bromo-5-fluoro-4-((4-methoxybenzyl)oxy)aniline (28.0 g, quantitative).¹H NMR (CDCl₃, 400 MHz) δ 7.34 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.4 Hz,1H), 6.91 (d, J=8.8 Hz, 2H), 6.58 (s, 1H), 4.95 (s, 2H), 3.89 (br. s.,2H), 3.82 (s, 3H).

2-bromo-5-fluoro-4-((4-methoxybenzyl)oxy)aniline (28.0 g, 86.0 mmol) inaqueous hydrochloric acid solution (1.0 N, 1400 mL) at 0° C. was treatedwith a solution of sodium nitrite (7.1 g, 103.0 mmol) in water (20 mL).The solution was stirred at 0° C. for 30 min. A solution of potassiumiodide (42.9 g, 258.0 mmol) in water (50 mL) was added and the solutionwas stirred for 30 mins at room temperature. The solution was dilutedwith ethyl acetate (200 mL) and quenched with an aqueous sodiumthiosulfate solution (1.0 N, 500 mL), and the organic phase wasseparated. The organic layer was washed with aqueous hydrochloric acidsolution (1.0 N, 100 mL), brine (100 mL), dried over sodium sulfate, andconcentrated to give 5-bromo-2-fluoro-4-iodophenol (20.0 g, yield 50.0%)as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.54 (d, J=9.6 Hz, 1H), 7.32(d, J=8.4 Hz, 1H), 5.33 (br. s., 1H).

MOMCl (7.3 g, 88.8 mmol) was added to a solution of5-bromo-2-fluoro-4-iodophenol (14.0 g, 44.4 mmol) and potassiumcarbonate (24.0 g, 177.0 mmol) in acetonitrile (150 mL) at 0° C. Themixture was stirred at room temperature for one hour. Water was added tomixture, and the aqueous was treated with EtOAc. The crude product waspurified by flash column chromatography (Petroleum ether:EtOAc=20:1-10:1) to give 1-bromo-4-fluoro-2-iodo-5-(methoxymethoxy)benzene (10.0g, yield 62.5%). ¹H NMR (CDCl₃, 400 MHz) δ 7.55 (d, J=10.0 Hz, 1H), 7.48(d, J=7.6 Hz, 1H), 5.20 (s, 2H), 3.52 (s, 3H).

A solution of 1-bromo-4-fluoro-2-iodo-5-(methoxymethoxy)benzene (9.3 g,25.7 mmol) in toluene (50 mL) was cooled to −40° C., then i-PrMgCl (19.3mL, 38.6 mmol) was added dropwise. An hour later DMF (5.6 g, 77.0 mmol)was added dropwise. The mixture was quenched by addition of water. Andthe organic phase was separated. The organic layer was washed with brine(100 mL), dried over sodium sulfate, and concentrated to give2-bromo-5-fluoro-4-(methoxymethoxy)benzaldehyde (5.6 g, yield 83.5%) asa white solid. ¹H NMR (CDCl₃, 400 MHz) δ. 10.19 (d, J=3.6 Hz, 1H), 7.67(d, J=10.6 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 5.31 (s, 2H), 3.54 (s, 3H).

2-bromo-5-fluoro-4-(methoxymethoxy)benzaldehyde (2.6 g, 10.0 mmol),Pd(dppf)Cl₂ (0.4 g, 0.5 mmol), Pin₂B₂ (3.0 g, 12.0 mmol) and KOAc (2.9g, 30.0 mmol) in dioxane (30 mL) were stirred at 80° C. overnight. LCMSshowed main peak as TM. The solvent was evaporated and the residue waspurified by flash column chromatography (Petroleumether:EtOAc=20:1-10:1) to give5-fluoro-4-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(2.4 g, yield 77.0%). ¹H NMR (CDCl₃, 400 MHz) δ 10.51 (d, J=3.2 Hz, 1H),7.73 (d, J=11.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 5.35 (s, 2H), 3.54 (s,3H), 1.38 (s, 12H).

Anhydrous MeOH was added to a solution of5-fluoro-4-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(2.4 g, 7.7 mmol) and NaBH₄ (0.6 g, 15.5 mmol) in THF (50 mL) at 0° C.The mixture was stirred at ambient temperature for 2 hours, TLC shownthat5-fluoro-4-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehydeconsumed. 1 N HCl was added to the mixture until pH=4, the aqueous layerwas treated with EtOAc, the organic layer was concentrated to give5-fluoro-6-(methoxymethoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (2.0 g crude)and used directly.

5-fluoro-6-(methoxymethoxy)benzo[c][1,2]oxaborol-1 (3H)-ol (2.0 g,crude) was dissolved in THF (20 mL) and 2N HCl (20 mL). The mixture wasstirred at room temperature for 3 hours. LCMS showed main peak as TM.The crude product was recrystallized from DCM/Petroleum ether (˜1:10) togive 5-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (300.0 mg, yield 20.0%)and 257.0 mg delivered. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.75 (s, 1H), 9.10(s, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.18 (d, J=11.2 Hz, 1H), 4.85 (s, 2H).MS: 167 (M−1)⁻

Tos-pleuromutilin (0.4 g, 0.8 mmol),5-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (0.1 g, 0.8 mmol) and K₂CO₃(0.2 g, 1.2 mmol) in 10 mL DMF was heated at 50° C. overnight. Main peakon LCMS was desired product. Water was added and the mixture was adjustto pH<4 with 2N aqueous HCl. White solid precipitated and the mixturewas filtered, the crude product was purified by Prep-HPLC (column: LunaC18 250×30 mm, 10 μm; liquid phase: [A-TFA/H₂O=0.1% v/v; B-ACN] B %:40%-65%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(255.0 mg, yield 57.0%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.10(s, 1H), 7.35-7.26 (m, 2H), 6.08 (dd, J=18.0, 11.2 Hz, 1H), 5.58 (d,J=7.6 Hz, 1H), 5.09-4.96 (m, 2H), 4.90 (s, 2H), 4.85-4.74 (m, 2H), 4.52(d, J=6.0 Hz, 1H), 3.43-3.38 (m, 1H), 2.41 (s, 1H), 2.25-1.96 (m, 6H),1.73-1.20 (m, 9H), 1.03 (s, 3H), 0.81 (d, J=6.8 Hz, 3H), 0.61 (d, J=6.8Hz, 3H). MS: 527 (M−1)⁻

4.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a stirred suspension of 1-bromo-3-fluoro-5-methoxybenzene (5.0 g, 25mmol) in DCM (50 mL) was added BBr₃ (12.2 g, 50 mmol) at −78° C. Theresulting mixture was stirred at −78° C. to r.t for 3 hrs, then themixture was poured into ice-water and extracted with EtOAc. The organicswas dried and concentrated to give 3-bromo-5-fluorophenol (4 g, 85%yield) as yellow oil. ¹H NMR: (CDCl3 400 MHz) δ 6.82-6.80 (m, 2H),6.53-6.51 (m, 1H), 6.20-6.15 (m, 1H).

To a stirred suspension of 3-bromo-5-fluorophenol (4.5 g, 23.7 mmol) wasadded Cs₂CO₃ (15.5 g, 47.4 mmol) and BnBr (4.5 g, 26 mmol) in dry CH₃CN(50 mL). The resulting mixture was stirred at 80° C. 3 h, and then, themixture was poured into water and extracted with EtOAc. The organics wasdried and concentrated to give a residue, which was purified by silicagel chromatography (petroleum ether:EtOAc=100:1 to 6:1) to give1-(benzyloxy)-3-bromo-5-fluorobenzene (4 g, 61.6% yield) as a white oil.

To a stirred suspension of 1-(benzyloxy)-3-bromo-5-fluorobenzene (15 g,54 mmol) in THF (500 mL) was added LDA (64 mL, 0.13 mol) at −78° C. Themixture was stirred at −78° C. 2 hrs, and then DMF (11.7 g, 0.16 mol)was added to the solution. The resulting mixture was stirred at −78° C.to r.t for 2 hrs, and then, the mixture was poured into ice-water andextracted with EtOAc. The organics was dried and concentrated to give aresidue, which was purified by silica gel chromatography (petroleumether:EtOAc=100:1 to 5:1) to give4-(benzyloxy)-2-bromo-6-fluorobenzaldehyde (6 g, 36.1% yield) as yellowoil.

A stirred mixture of 4-(benzyloxy)-2-bromo-6-fluorobenzaldehyde (2.5 g,8.0 mmol) and NaBH₄ (0.58 g, 14.6 mmol) in MeOH (20 mL) was stirred at0° C. for 1 h. The mixture was adjusted pH to 6-7, extracted with EtOAc.The organic layers were dried and concentrated to give(4-(benzyloxy)-2-bromo-6-fluorophenyl) methanol (2.3 g, 88%).

To a stirred suspension of (4-(benzyloxy)-2-bromo-6-fluorophenyl)methanol (2.3 g, 6.7 mmol) and DIEA (1.7 g, 13.5 mmol) in dry DCM (20mL) was added MOMCl (0.68 g, 8.5 mmol) dropwise at 0° C. The resultingmixture was stirred at 0° C. for 2 hrs, and then, the mixture was pouredinto water and extracted with EtOAc. The organics was dried andconcentrated to give a residue, which was purified by silica gelchromatography (petroleum ether:EtOAc=100:1 to 3:1) to give5-(benzyloxy)-1-bromo-3-fluoro-2-((methoxymethoxy)methyl)benzene (1.6 g,67.6% yield) as white oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.41-7.34 (m, 5H),7.06 (s, 1H), 6.69-6.66 (m, 1H), 5.03 (s, 2H), 4.71 (s, 2H), 4.68 (s,2H), 3.42 (s, 3H).

To a stirred suspension of5-(benzyloxy)-1-bromo-3-fluoro-2-((methoxymethoxy)methyl)benzene (2 g,5.6 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(2.2 g, 8.5 mmol) and KOAc (1.6 g, 16.8 mmol) in dry dioxane (20 mL),was added Pd(dppf)Cl₂ (0.41 g, 0.56 mmol) under N₂. The resultingmixture was stirred at 80° C. 5 h under N₂, and then, the mixture waspoured into water and extracted with EtOAc. The organics was dried andconcentrated to give a crude2-(5-(benzyloxy)-3-fluoro-2-((methoxymethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.9 g, 84% yield) as yellow oil.

A stirred suspension of2-(5-(benzyloxy)-3-fluoro-2-((methoxymethoxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2 g, 4.9 mmol) in HCl/THF (2M/L, 10 mL) was stirred at 60° C. for 10hrs, and then, the mixture was poured into water and extracted withEtOAc. The organics was dried and concentrated to give a crude product,which was purified with prep-HPLC to give6-(benzyloxy)-4-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.5 g, 39.6%yield) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.38 (s, 1H),7.46-7.44 (m, 2H), 7.39-7.38 (m, 2H), 7.35-7.33 (m, 1H), 7.17 (s, 1H),7.03-7.00 (m, 1H), 5.14 (s, 2H), 4.99 (s, 2H). MS (ESI): mass calcd. forC₁₄H₁₂BFO₃ 258.09, m/z found 257.0 [M−1]⁻. HPLC: 95.1% (220 nm), 83.4%(254 nm).

To a stirred suspension of6-(benzyloxy)-4-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.5 g, 1.94 mmol)in propan-2-ol (10 mL) was added Pd/C (0.4 g). The resulting mixture wasstirred at r.t for 15 hrs under H₂, and then, the mixture was filteredand concentrated to give 4-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol(0.3 g, 92% yield) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.79(s, 1H), 9.28 (s, 1H), 6.96 (s, 1H), 6.67-6.64 (m, 2H), 4.94 (s, 2H). MS(ESI): mass calcd. for C₇H₆BFO₃ 168.04, m/z found 167.1 [M−1]⁻. HPLC:98.9% (220 nm), 100% (254 nm).

A stirred mixture of 4-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (150mg, 0.9 mmol) and Tos-pleuromutilin (570 mg, 1.1 mmol) and K₂CO₃ (370mg, 2.7 mmol) in DMF (5 mL) was stirred at 50° C. for 3 hrs. The mixturewas then diluted with water and extracted with EtOAc The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to give the crude product which was purified with prep-HPLC(column: Luna C18 100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v;B-ACN] B %: 40%-70%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(63 mg, 13.4%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.29-9.24(br. s., 1H), 7.08 (s, 1H), 6.93 (d, J=11.2 Hz, 1H), 6.15-6.05 (m, 1H),5.60-5.56 (d, J=8.8 Hz, 1H), 5.05-4.99 (m, 4H), 4.77-4.75 (d, J=8.0 Hz,2H), 2.41 (s, 1H), 2.41-2.04 (m, 4H), 1.63-1.41 (m, 4H), 1.33-1.28 (m,7H), 1.04-0.85 (m, 4H), 0.81 (d, J=6.4 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H).MS (ESI): mass calcd. for C₂₉H₃₈BFO₇ 528.27, m/z found 527.2 [M−1]⁻.HPLC: 96.0% (220 nm), 69.6% (254 nm).

5.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5,7-difluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of 3,4,5-trifluorobenzoic acid (40.0 g, 227.2 mmol, 1.0eq.) in THF (1 L) was added n-BuLi (2.5 M, 227.2 mL, 2.5 eq.). Themixture was stirred at −78° C. for 2.5 hrs, then 12 (144.1 g, 567.9mmol, 2.5 eq.) (in 500 mL THF) was added dropwise, the mixture wasstirred at −78° C. for 0.5 hr. TLC indicated 3,4,5-trifluorobenzoic acidwas consumed completely, one new spot formed. The reaction mixture wasquenched by addition saturated Na₂S₂O₃ 500 mL, and then extracted withEtOAc 1500 mL (500 mL×3). The combined organic layers were washed withbrine 600 mL, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. 3,4,5-trifluoro-2-iodobenzoic acid (45.0 g,149.0 mmol, 65.6% yield) was obtained as a white solid. ¹H NMR (CDCl₃,400 MHz) δ 7.90-7.77 (m, 1H)

To a solution of 3,4,5-trifluoro-2-iodobenzoic acid (30.0 g, 99.3 mmol,1.0 eq.) in EtOH (300.0 mL) was added con.H₂SO₄ (99.3 mmol, 1.0 eq.).The mixture was stirred at 90° C. for 16 hours. TLC indicated the3,4,5-trifluoro-2-iodobenzoic acid was consumed completely. The reactionmixture was concentrated under reduced pressure to remove EtOH. Theresidue was diluted with H₂O 300 mL and extracted with DCM 600 mL (200mL×3). The combined organic layers were washed with brine 300 mL, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=10/1). ethyl3,4,5-trifluoro-2-iodobenzoate (32.0 g, 96.9 mmol, 97.6% yield) wasobtained as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.64 (ddd, J=2.0,7.5, 10.0 Hz, 1H), 4.44 (q, J=7.4 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).

To a solution of ethyl 3,4,5-trifluoro-2-iodobenzoate (13.0 g, 39.4mmol, 1.0 eq.) and phenylmethanol (6.4 g, 59.1 mmol, 1.5 eq.) in DMF(10.00 mL) was added K₂CO₃ (6.5 g, 47.3 mmol, 1.2 eq.). The mixture wasstirred at 25° C. for 18 hours. TLC indicated a main new pot was formed,but ethyl 3,4,5-trifluoro-2-iodobenzoate remained. The reaction mixturewas quenched by addition H₂O 200 mL, and then extracted with EtOAc 600mL (200 mL×3). The combined organic layers were washed with brine 200mL, dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=50/1). ethyl4-(benzyloxy)-3,5-difluoro-2-iodobenzoate (10.0 g, 23.9 mmol, 60.7%yield) was obtained as colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ7.57-7.48 (m, 1H), 7.46-7.30 (m, 5H), 5.27 (s, 2H), 4.39 (q, J=7.4 Hz,2H), 1.41 (t, J=7.0 Hz, 3H).

To a solution of ethyl 4-(benzyloxy)-3,5-difluoro-2-iodobenzoate (5.0 g,11.9 mmol, 1.0 eq.), Pin₂B₂ (24.3 g, 95.7 mmol, 8.0 eq.) and AcOK (2.7g, 27.5 mmol, 2.3 eq.) in dioxane (50.0 mL) was added Pd(PPh₃)₂Cl₂(167.9 mg, 239.2 umol, 0.02 eq.). The mixture was stirred at 120° C. for40 hours. HPLC indicated ethyl 4-(benzyloxy)-3,5-difluoro-2-iodobenzoatewas consumed completely. The reaction mixture was filtered to removeAcOK, then filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=100/1). ethyl4-(benzyloxy)-3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(20.0 g, crude) (mixed Pin₂B₂) was obtained as a white solid. ¹H NMR(CDCl₃, 400 MHz) δ 7.52-7.29 (m, 6H), 5.20 (s, 2H), 4.33 (q, J=7.4 Hz,2H), 1.41 (s, 12H), 1.34 (t, J=7.3 Hz, 3H).

To a solution of ethyl4-(benzyloxy)-3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(20.0 g, 4.8 mmol, 1.0 eq.) in THF (150.0 mL) was added NaBH₄ (180.9 mg,4.8 mmol, 1.0 eq). The mixture was stirred at 25° C. for 5 hours. TLCindicated ethyl4-(benzyloxy)-3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoatewas consumed completely. The reaction mixture was quenched by additionH₂O 100 mL, and then adjusted pH=6, removed THF, solid was dissolvedout, filtered and concentrated under reduced pressure to give a residue.The residue was washed with Petroleum ether, then suspended withpetroleum ether, filtrated to give desired product.6-(benzyloxy)-5,7-difluorobenzo[c][1,2]oxaborol-1(3H)-ol (1.3 g, 4.7mmol, 98.5% yield) was obtained as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.46 (d, J=6.5 Hz, 2H), 7.41-7.33 (m, 3H), 6.89 (d, J=8.5 Hz,1H), 5.17 (s, 2H), 5.01 (s, 2H).

To a solution of6-(benzyloxy)-5,7-difluorobenzo[c][1,2]oxaborol-1(3H)-ol (100.0 mg,362.3 umol, 1.0 eq.) in EtOAc (50.0 mL) was added Pd/C (200.0 mg). Themixture was stirred at 25° C. for 4 hours under H₂ atmosphere (50 psi).TLC indicated 6-(benzyloxy)-5,7-difluorobenzo[c][1,2]oxaborol-1(3H)-olwas consumed completely. The reaction mixture was filtered andconcentrated under reduced pressure to give a desired.5,7-difluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (60.0 mg, 322.7 umol,89.1% yield) was obtained as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ9.92 (s, 1H), 9.23 (s, 1H), 7.10 (d, J=10.0 Hz, 1H), 4.88 (s, 2H)

To a solution of 5,7-difluorobenzo[c][1,2]oxaborole-1,6(3H)-diol (300.0mg, 1.6 mmol, 1.0 eq.) and pleur-tosylate (786.3 mg, 1.6 mmol, 1.0 eq)in DMSO (12.0 mL) was added Na₂CO₃ (341.3 mg, 3.2 mmol, 2.0 eq). Themixture was stirred at 30° C. for 16 hours. HPLC indicated5,7-difluorobenzo[c][1,2]oxaborole-1,6(3H)-diol was consumed completely.The reaction mixture was quenched by addition H₂O 30 mL, and thenadjusted pH=6. Solid was precipitated, and filtered to give a residue.The residue was purified by prep-HPLC column: Phenomenex luna (2) C18250×50 mm, 10 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %:35%-65%, 20 min], removed CH₃CN, then freeze-drying to give the desiredproduct.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5,7-difluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (308.0 mg, 563.8 umol, 35.0% yield) was obtained as a lightyellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.16 (d, J=10.1 Hz, 1H), 6.05(dd, J=11.5, 17.6 Hz, 1H), 5.57 (d, J=7.9 Hz, 1H), 4.97 (d, J=6.6 Hz,1H), 4.93 (s, 1H), 4.89 (s, 2H), 4.71 (d, J=19.0 Hz, 2H), 3.36 (d, J=6.2Hz, 1H), 2.34 (br. s., 1H), 2.20-2.09 (m, 1H), 2.08-1.94 (m, 3H),1.67-1.51 (m, 3H), 1.41 (d, J=17.2 Hz, 1H), 1.36-1.14 (m, 6H), 1.03-0.90(m, 4H), 0.78 (d, J=7.1 Hz, 3H), 0.53 (d, J=6.6 Hz, 3H). MS (ESI): masscalcd. For C₂₉H₃₇BF₂NO₇ 546.3, m/z found 545.2 [M−H]⁻. HPLC: 97.3% (220nm), 94.0% (254 nm).

6.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

Sodium hydride (60% in oil, 190 mg, 4.76 mmol) was added to a solutionof 7-chlorobenzo[c][1,2]oxaborole-1,5(3H)-diol (330 mg, 1.79 mmol) in 5mL of DMF. After the suspension was stirred at 50° C. for two hours, asolution of Tos-pleuromutilin (634 mg, 1.19 mmol) in 5 mL DMF was added.The mixture was stirred at room temperature overnight. The crude waspurified by prep HPLC (column: SunFire C18 OBD 100×30 mm, 5 μm) elutedwith gradient water/acetonitrile (0.1% TFA) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetateas white flakes. ¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 7.18 (d, J=8Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.04 (dd, J=17.6, 11.2 Hz, 1H), 5.53(d, J=7.2 Hz, 1H), 5.02 (m, 2H), 4.84 (s, 2H), 4.79 (s, 2H), 4.49 (d,J=6.4 Hz, 1H), 3.35 (m, 1H), 2.35 (s, 1H), 2.11-1.96 (m, 4H), 1.61-1.17(m, 10H), 0.98-0.93 (m, 4H), 0.74 (d, J=6.8 Hz, 3H), 0.58 (d, J=6.8 Hz,3H). MS (ESI): mass calcd. For C₂₉H₃₈BO₇Cl 544.87, m/z found 543.2[M−H]⁻. HPLC: 100% (220 nm), 100% (254 nm).

7.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate8.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of 3,5-dibromo-4-methylphenol (10 g, 38 mmol) and DIPEA(14 mL, 76 mmol) in DCM (150 mL) was added (chloromethoxy)ethane (5.4mL, 57 mmol). The reaction mixture was heated to reflux overnight. Aftercooled to r.t, water (150 mL) was added and the mixture was extractedwith DCM (150 mL×2). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under the reduced pressure.The residue was purified by silica gel column chromatography usingpetroleum ether:ethyl acetate=20:1 as eluent to give1,3-dibromo-5-(ethoxymethoxy)-2-methylbenzene (10 g, yield 82%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.24 (s, 2H), 5.16 (s, 2H),3.70 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 1.22 (t, J=6.8 Hz, 3H).

To a solution of 1,3-dibromo-5-(ethoxymethoxy)-2-methylbenzene (1.5 g,4.66 mmol) in pyridine:DMF (1:2) (30 mL) was added CuCN (419 mg, 4.66mmol). The reaction mixture was heated to 140° C. overnight. Aftercooled to room temperature, EA (150 mL) and ammonia water (50 mL) wereadded. The mixture was washed with water (100 mL×3). The solvent wasremoved and the residue was purified by silica gel column chromatographyusing petroleum ether:ethyl acetate=15:1 to give3-bromo-5-(ethoxymethoxy)-2-methylbenzonitrile (520 mg, yield 41%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J=2.4 Hz, 1H), 7.26 (d,J=2.4 Hz, 1H), 5.19 (s, 2H), 3.71 (q, J=7.2 Hz, 2H), 2.55 (s, 3H), 1.22(t, J=7.2 Hz, 3H).

To a solution of 3-bromo-5-(ethoxymethoxy)-2-methylbenzonitrile (1.72 g,6.37 mmol) and NBS (1.1 g, 6.37 mmol) in CCl₄ (30 mL) was added AIBN(104 mg, 0.637 mmol). The reaction mixture was heated to refluxovernight. The solvent was removed and the residue was purified bysilica gel column chromatography using petroleum ether:ethylacetate=15:1 to give3-bromo-2-(bromomethyl)-5-(ethoxymethoxy)benzonitrile (1.2 g, yield 54%)as a colorless oil. It was used in next step without furtherpurification.

To a solution of 3-bromo-2-(bromomethyl)-5-(ethoxymethoxy)benzonitrile(1.2 g, 3.44 mmol) in DMF (30 mL) was added NaOAc (564 mg, 6.88 mmol).The reaction mixture was heated to 50° C. for 1 h, then EA (150 mL) wasadded. The mixture was washed with water (50 mL×3). The solvent wasremoved and the residue was purified by silica gel column chromatographyusing petroleum ether:ethyl acetate=6:1 to give2-bromo-6-cyano-4-(ethoxymethoxy)benzyl acetate (950 mg, yield 84%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.34 (s, 1H), 5.32(s, 2H), 5.24 (s, 2H), 3.72 (q, J=7.2 Hz, 2H), 2.11 (s, 3H), 1.23 (t,J=7.2 Hz, 3H). MS (ESI): mass calcd. For C₁₃H₁₄BrNO₄ 327.01, m/z found350.0 [M+Na]⁺.

To a solution of 2-bromo-6-cyano-4-(ethoxymethoxy)benzyl acetate (200mg, 0.61 mmol), Pin₂B₂ (310 mg, 1.22 mmol) and KOAc (179 mg, 1.83 mmol)in 1,4-dioxane (5 mL) was added PdCl₂(dppf)₂ (22 mg, 0.03 mmol). Thereaction mixture was stirred at 80° C. under argon atmosphere overnight.The solvent was removed and the residue was purified by columnchromatography on silica gel by elution with petroleum ether:ethylacetate=6:1 to give2-cyano-4-(ethoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (140 mg, yield 61%) as a colorless oil. MS (ESI): mass calcd.For C₁₉H₂₆BNO₆ 375.17, m/z found 398.2 [M+Na]⁺.

A mixture of2-cyano-4-(ethoxymethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (1 g, 2.67 mmol), NaOH (213 mg, 5.3 mmol) in H₂O (5 mL) and THF(20 mL) was stirred at r.t for 3 h, Then the mixture was added HCl (6N)to pH=3, the mixture was stirred r.t for 3 h. Water (20 mL) was addedand the solution was extracted with EA (100 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under thereduced pressure. The residue was purified by Combiflash to give6-(ethoxymethoxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-4-carbonitrile(280 mg, yield 45%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 9.55(s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 5.32 (s, 2H),5.10 (s, 2H), 3.67 (q, J=6.0 Hz, 2H), 1.13 (t, J=6.0 Hz, 3H

To a solution of tert-butyl(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate (75mg, 0.27 mmol) in DMF (3 mL) was added NCS (36 mg, 0.27 mmol). Thereaction mixture was heated to 50° C. for 2 h. Then the mixture waspurified by prep-HPLC to give tert-butyl(7-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate(50 mg, yield 60%) as a white solid. MS (ESI): mass calcd. ForC₁₃H₁₇BClNO₅ 313.54, m/z found 214.1 [M−99]⁺.

To a solution of tert-butyl(7-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate(40 mg, 0.128 mmol), KI (4 mg, 0.026 mmol) and K₂CO₃ (35 mg, 0.255 mmol)in MeCN (3 mL) was added TsO-Pleu (82 mg, 0.153 mmol). The reactionmixture was heated to reflux overnight. After removed the solvent, theresidue was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(42 mg, yield 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.11(s, 1H), 7.28 (t, J=5.2 Hz, 1H), 7.03 (s, 1H), 6.13-6.09 (m, 1H), 5.60(d, J=8.4 Hz, 1H), 5.11-5.02 (m, 2H), 4.94 (s, 2H), 4.78 (q, J=16.8 Hz,2H), 4.02 (d, J=5.2 Hz, 2H), 2.43 (s, 1H), 2.20-2.04 (m, 4H), 1.68-0.97(m, 24H), 0.82 (d, J=6.8 Hz, 3H), 0.65 (d, J=7.2 Hz, 3H). HPLC purity:100% (214 nm); MS (ESI): mass calcd. For C₃₅H₄₉BClNO₉ 673.32, m/z found695.8 [M+Na]⁺.

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(42 mg, 0.062 mmol) in DCM (5 mL) was added HCl/1,4-dioxane (4 N, 2.5mL). The reaction mixture was stirred at r.t for 3 h. The solvent wasremoved and the residue was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(22.2 mg, yield 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.04(s, 1H), 7.17 (s, 1H), 6.16-6.13 (m, 1H), 5.61 (d, J=8.0 Hz, 1H),5.11-5.01 (m, 2H), 4.97 (s, 2H), 4.822 (d, J=4.0 Hz, 2H), 4.54 (d, J=6.0Hz, 1H), 4.46-4.44 (m, 2H), 3.62 (s, 2H), 2.43 (s, 1H), 2.23-2.04 (m,4H), 1.68-0.97 (m, 14H), 0.81 (d, J=7.2 Hz, 3H), 0.66 (d, J=6.8 Hz, 3H).HPLC purity: 100% (214 nm); MS (ESI): mass calcd. For C₃₀H₄₁BClNO₇573.27, m/z found 573.8 [M+H]⁺.

9.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

7-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.2 g, 1.5 mmol),(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (0.8 g, 1.5 mmol) and K₂CO₃ (0.6 g, 4.4 mmol) in 5mL of DMF was heated at 50° C. overnight. Main peak on LCMS was desiredproduct. Water was added and the mixture was adjust to pH<4 with 2Naqueous HCl. White solid precipitated and the mixture was filtered, thecrude product was purified by prep-HPLC (column: Luna C18 250×30 mm, 10μm; liquid phase: [A-TFA/H₂O=0.1% v/v; B-ACN] B %: 35%-65%, 20 min]) togive(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(0.4 g, 54.0%). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.09 (d, J=8.0 Hz, 1H), 6.95(d, J=8.0 Hz, 1H), 6.11 (dd, J=17.6, 11.2 Hz, 1H), 5.61 (d, J=8.0 Hz,1H), 5.09-4.98 (m, 2H), 4.87 (s, 2H), 4.72 (d, J=2.0 Hz, 2H), 3.41 (d,J=5.6 Hz, 1H), 2.36 (s, 1H), 2.33 (s, 3H), 2.20-2.10 (m, 1H), 2.10-1.95(m, 4H), 1.72-1.55 (m, 2H), 1.54-1.36 (m, 2H), 1.34 (s, 3H), 1.31-1.15(m, 3H), 1.03 (s, 4H), 0.82 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H).MS: 523 (M−1)⁻.

10.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-5-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

A mixture of 1-fluoro-2-methyl-4-nitrobenzene (20.0 g, 129.0 mmol),PMBOH (17.8 g, 129 mmol) and potassium hydroxide (10.8 g, 194.0 mmol) in150 mL of acetonitrile were stirred overnight. Water was added to themixture, the mixture was filtered, washed with water and dried to give1-((4-methoxybenzyl)oxy)-2-methyl-4-nitrobenzene (32.1 g, yield 92.0%).¹H NMR (CDCl₃, 400 MHz) δ 8.10-8.07 (m, 2H), 7.37-7.35 (d, J=8.8 Hz,2H), 6.95-6.92 (m, 3H), 5.11 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H).

To a mixture of 1-((4-methoxybenzyl)oxy)-2-methyl-4-nitrobenzene (43.5g, 160.0 mmol), and ammonium chloride (25.6 g, 480.0 mmol) in 300 mL ofethanol and 50 mL of water was added iron powder (25.0 g, 450.0 mmol).The mixture was stirred at reflux for 2 hours. The mixture was filteredand washed with ethanol and the filtrate was evaporated, the crudeproduct was added to brine and extracted with ethyl acetate three times,then concentrated to give 4-((4-methoxybenzyl)oxy)-3-methylaniline (31.0g, yield 80.3%). ¹H NMR (CDCl₃, 400 MHz) δ 7.35-7.34 (d, J=8.8 Hz, 2H),6.92-6.90 (d, J=8.8 Hz, 2H), 6.74-6.72 (d, J=8.8 Hz, 1H), 6.56 (s, 1H),6.50-6.48 (s, 1H), 4.92 (s, 2H), 3.82 (s, 3H), 2.19 (s, 3H).

NBS (13.0 g, 73.2 mmol) was added in portions to a solution of4-((4-methoxybenzyl)oxy)-3-methylaniline (17.8 g, 73.2 mmol) in 500 mLDCM at −15° C., five minutes later, new spot formed and STM consumed.Water was added to the mixture and the aqueous layer was treated withDCM, the crude product was purified by silica column to give2-bromo-4-((4-methoxybenzyl)oxy)-5-methylaniline (8.0 g, yield 23.5%).¹H NMR (CDCl₃, 400 MHz) δ7.35 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 6.98 (s,2H), 6.92 (d, J=8.8 Hz, 2H), 6.63 (d, J=0.8 Hz, 1H), 4.90 (s, 2H),3.84-3.82 (m, 3H), 2.15 (s, 3H).

To a solution of 2-bromo-4-((4-methoxybenzyl)oxy)-5-methylaniline (12.0g, 37.2 mmol) in aqueous hydrochloric acid solution (1.0 N, 600 mL) wasadded a solution of sodium nitrite (3.4 g, 48.4 mmol) in water (10 mL)at 0° C. The solution was stirred at 0° C. for 30 min. A solution ofpotassium iodide (18.5 g, 111 mmol) in water (20 mL) was added and thesolution stirred 30 min at room temperature. The solution was dilutedwith ethyl acetate (200 mL) and quenched with an aqueous sodiumthiosulfate solution (1.0 N, 500 mL), and the organic phase wasseparated. The organic layer was washed with aqueous hydrochloric acidsolution (1.0 N, 100 mL), brine (100 mL), dried over sodium sulfate, andconcentrated to give1-bromo-2-iodo-5-((4-methoxybenzyl)oxy)-4-methylbenzene as a white solid(8.0 g, yield 50.0%). ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (d, J=0.8 Hz, 1H),7.34 (d, J=8.8 Hz, 2H), 7.15 (s, 1H), 6.95-6.90 (m, 2H), 4.96 (s, 2H),3.84 (s, 3H), 2.15 (s, 3H).

A solution of 1-bromo-2-iodo-5-((4-methoxybenzyl)oxy)-4-methylbenzene(0.5 g, 1.6 mmol) in toluene (20 mL) was cooled to −40° C., then asolution of i-PrMgCl (1 mL, 2.0 mmol) was added dropwise. An hour laterDMF (0.38 g, 5.3 mmol) was added to the mixture dropwise. After stirringfor 2 hrs at 0° C., the mixture was quenched by addition of water. Andthe organic phase was separated. The organic layer was washed with brine(100 mL), dried over sodium sulfate, and concentrated to give2-bromo-4-((4-methoxybenzyl)oxy)-5-methylbenzaldehyde as a white solid(0.2 g, yield 58.0%). ¹H NMR (CDCl₃, 400 MHz) δ 10.20 (s, 1H), 7.75 (s,1H), 7.77 (d, J=4.8 Hz, 1H), 7.11 (s, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.08(s, 2H), 3.84 (s, 3H), 2.22 (s, 3H).

A mixture of 2-bromo-4-((4-methoxybenzyl)oxy)-5-methylbenzaldehyde (2.5g, 7.5 mmol), Pd(dppf)Cl₂ (0.3 g, 0.4 mmol), Pin₂B₂ (2.8 g, 9.0 mmol)and KOAc (2.2 g, 22.4 mmol) in dioxane (30 mL) was stirred at 80° C.overnight. LCMS showed main peak as desired compound. The solvent wasevaporated to give crude product, which was purified by flash columnchromatography (Petroleum ether:EA=0-10:1) to give4-((4-methoxybenzyl)oxy)-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1.7 g, yield 58.5%) as white solid. ¹H NMR (CDCl₃, 400 MHz) δ10.47 (s,1H), 7.83 (s, 1H), 7.43-7.33 (m, 3H), 6.98-6.91 (m, 2H), 5.13 (s, 2H),3.84 (s, 3H), 2.29 (s, 3H), 1.40 (s, 12H).

Anhydrous MeOH (5 mL) was added to a solution of4-((4-methoxybenzyl)oxy)-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1.7 g, 4.3 mmol) and NaBH₄ (0.3 g, 8.7 mmol) in THF (20 mL) at 0° C.The mixture was stirred at ambient temperature for 30 mins. 1 N aq. HClwas added to the mixture until pH=4, the aqueous layer was treated withEtOAc, the organic layer was concentrated to give6-((4-methoxybenzyl)oxy)-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.7 g,yield 57.0%) and used directly into next step.

6-((4-methoxybenzyl)oxy)-5-methylbenzo[c][1,2]oxaborol-1 (3H)-ol (1.7 g,7.0 mmol) was dissolved in EtOAc (80 mL). To this solution undernitrogen was added Pd/C (0.5 g). The reaction mixture was vacuumed andbackfilled hydrogen for 3 times, then hydrogenated at room temperature,50 psi overnight. After filtration and rotary evaporation, the residuewas purified by recrystallization (DCM/Petroleum Ether, 1:10) to give5-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (300.0 mg, 31.5% yield) and151.0 mg delivered. δ 9.22 (d, J=1.6 Hz, 1H), 8.94 (d, J=1.6 Hz, 1H),7.08 (d, J=4.8 Hz, 1H), 4.82 (s, 2H), 2.15 (s, 3H). MS: 163 (M−1)⁻

Tos-pleuromutilin (420.0 mg, 0.8 mmol), 5-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (130.0 mg, 0.8 mmol) and K₂CO₃ (330.0 g,2.3 mmol) in 20 mL DMF was heated at 50° C. overnight. Main peak on LCMSwas desired product. Water was added and the mixture was adjust to pH<4with 2N aqueous HCl. White solid precipitated and the mixture wasfiltered, the crude product was purified by prep-HPLC (column: Luna C18250×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.1% v/v; B-ACN] B %: 40%-70%,20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-5-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(78.0 mg, yield 19.0%). δ 8.93 (br. s., 1H), 7.19 (s, 1H), 7.09 (s, 1H),6.08 (dd, J=17.6, 11.2 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.12-4.95 (m,2H), 4.87 (s, 2H), 4.71 (s, 2H), 3.40 (d, J=4.8 Hz, 1H), 2.40 (s, 1H),2.25 (s, 3H), 2.20-1.96 (m, 3H), 1.74-1.55 (m, 2H), 1.50-1.45 (m, 1H),1.37 (s, 3H), 1.45-1.17 (m, 6H), 1.10-0.94 (m, 4H), 0.82 (d, J=6.4 Hz,3H), 0.62 (d, J=6.4 Hz, 3H). MS: 523 (M−1)⁻

11.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

5-methylbenzene-1,3-diol (25.0 g, 0.2 mol) in DMF (100 mL) was addeddropwise to a mixture of POCl₃ (44.0 g, 0.3 mol) in DMF (200 mL) at 0°C., the mixture was stirred at room temperature for 1 hr, then thereaction mixture was poured into ice water, solid precipitated and themixture was filtered and washed with water three times, dried to give2,4-dihydroxy-6-methylbenzaldehyde (21.0 g, 82.0%), which was used fornext step directly.

BnBr (15.24 mL, 0.128 mol) was added to a mixture of2,4-dihydroxy-6-methylbenzaldehyde (19.5 g, 0.1 mol) and NaHCO₃ (10.8 g,0.1 mol) in MeCN (200 mL) at room temperature and the mixture was thenrefluxed at 90° C. for 48 hrs. The solvent was removed under reducedpressure and the residue was poured into cold water, extracted withEtOAc twice, the combined organic layers were dried over Na₂SO₄,concentrated and then purified by column chromatography (EtOAc/Petroleumether, 1:10-1:5) to give 4-(benzyloxy)-2-hydroxy-6-methylbenzaldehyde(23.6 g, 76.0%). ¹H NMR (MeOD, 400 MHz) δ 10.13 (s, 1H), 7.24-7.59 (m,5H), 6.26-6.51 (m, 2H), 5.13 (s, 2H), 2.54 (s, 3H).

To a solution of 4-(benzyloxy)-2-hydroxy-6-methylbenzaldehyde (13.6 g,560.0 mmol) and TEA (19.0 mL) in dry DCM (200 mL) was added Tf₂₀ (14.2mL, 840.0 mmol) dropwise at 0° C. The mixture was stirred at roomtemperature for 4 hrs. Then water was added, adjusted pH to 3-4,extracted with DCM, purified by column chromatography (EtOAc/Petroleumether, 1:10˜1:5) to give 5-(benzyloxy)-2-formyl-3-methylphenyltrifluoromethanesulfonate (15.0 g, 71.0%). ¹H NMR (CDCl₃, 400 MHz) δ10.35 (s, 1H), 7.43-7.38 (m, 7H), 5.14 (s, 2H), 2.66 (s, 3H).

A mixture of 5-(benzyloxy)-2-formyl-3-methylphenyltrifluoromethanesulfonate (2.0 g, 5.3 mmol), Pin₂B₂ (1.4 g, 5.6 mmol),Pd(dppf)Cl₂ (0.1 g, 0.2 mmol) and KOAc (1.6 g, 16.0 mmol) in dioxane (20mL) was bubbled with nitrogen for 10 mins, then the mixture was stirredovernight at 80° C. under a N₂ balloon. The solvent was removed and theresidue was purified by silica gel chromatography (EtOAc/Petroleumether, 1:20˜1:5) to give4-(benzyloxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1.0 g, 53.0%). ¹H NMR (CDCl₃, 400 MHz) δ 10.34 (s, 1H), 7.32-7.47 (m,5H), 7.06 (d, J=2.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 5.13 (s, 2H), 2.63(s, 3H), 1.43 (s, 12H).

To a stirred solution of4-(benzyloxy)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1 g, 2.8 mmol) in dry THF (10 mL) was added NaBH₄ (0.2 g, 5.7 mmol),MeOH (0.5 mL). The mixture was stirred at room temperature for 2 hrs.Then water was added, the mixture was extracted with EtOAc, evaporatedto give 6-(benzyloxy)-4-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.8 gcrude). ¹H NMR (MeOD, 400 MHz) δ 7.46-7.33 (m, 5H), 7.14 (s, 1H), 6.96(s, 1H), 5.10 (s, 2H), 4.00 (s, 2H), 2.25 (s, 3H).

To a stirred solution of 6-(benzyloxy)-4-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added Pd/C (0.2 g) andthe mixture was stirred under hydrogen atmospheres (50 psi) overnight.The mixture was filtered through celite and the filtrate wasconcentrated, recrystallized with DCM/petroleum ether (1:5) to give thedesired product as white solid (0.4 g, 78.0% yield). ¹H NMR (DMSO-d₆,400 MHz) δ 9.16 (s, 1H), 8.98 (s, 1H), 6.91 (s, 1H), 6.68 (s, 1H), 4.83(s, 2H), 2.13 (s, 3H). MS: 163 (M−1)⁻

4-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.3 g, 1.8 mmol),(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (1.0 g, 1.8 mmol) and K₂CO₃ (0.8 g, 5.5 mmol) in 5mL DMF was heated at 50° C. overnight. Main peak on LCMS was desiredproduct. Water was added and the mixture was adjust to pH<4 with 2N HCl,White solid precipitated and filtered, the crude product was purified byprep-HPLC (column: Luna C18 250×30 mm, 10 μm; liquid phase:[A-TFA/H₂O=0.1% v/v; B-ACN] B %: 35%-65%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(0.2 g, 22.0%). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.02 (d, J=1.76 Hz, 1H),6.83 (d, J=1.76 Hz, 1H), 6.10 (dd, J=17.6, 11.2 Hz, 1H), 5.60 (d, J=8.4Hz, 1H), 5.12-4.96 (m, 2H), 4.87 (s, 2H), 4.75-4.60 (m, 2H), 2.41 (br.s., 1H), 2.17 (s, 3H), 2.00-2.13 (m, 5H), 1.72-1.55 (m, 2H), 1.54-1.39(m, 2H), 1.35 (s, 3H), 1.32-1.20 (m, 3H), 1.04 (m, 4H), 0.82 (d, J=6.4Hz, 3H), 0.64 (d, J=7.2 Hz, 3H). MS: 523 (M−1)⁻

12.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetateHydrochloride

A mixture of tert-butyl((1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl) methyl)carbamate(1.6 g, 5.8 mmol, 1.0 equiv), pleuromutilintosylate (3.4 g, 7.0 mmol,1.2 equiv) and K₂CO₃ (2.4 g, 17.5 mmol, 3.0 equiv) in DMSO (50.0 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 80° C. for 12 hours under N₂ atmosphere. The mixture waspoured into ice-water and the solid was filtered, which was purified byprep-HPLC (column: Luna 250×50.0 mm, 5 μm; liquid phase: [A-H₂O+0.075%TFA; B-ACN] B %: 35%-65%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(1.3 g, 2.0 mmol, 34.8% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.08 (s, 1H), 7.36 (s, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.13-6.06(m, 1H), 5.58 (d, J=10.8 Hz, 1H), 5.10-4.99 (m, 2H), 4.93 (s, 2H), 4.68(q, J=16.8 Hz, 2H), 4.06-4.04 (m, 2H), 3.42-3.41 (m, 2H), 2.41 (s, 1H),2.18-1.05 (m, 27H), 0.82 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H).

A mixture of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(1.6 g, 2.5 mmol, 1.0 equiv) in HCl/EtOAc (20.0 mL) was stirred at 25°C. for 4 hours then solid precipitated. The mixture was filtered tocollect the solid.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(1.18 g, 2.05 mmol, 81.95% yield) was obtained as an off-white solid. ¹HNMR (DMSO-d₆, 400 MHz) δ 9.19 (s, 1H), 8.30 (br. s., 3H), 7.26-7.17 (m,2H), 6.11 (dd, J=11.2, 17.9 Hz, 1H), 5.62 (d, J=8.8 Hz, 1H), 5.15-4.95(m, 4H), 4.79-4.65 (m, 2H), 4.55 (br. s., 1H), 3.93 (d, J=5.3 Hz, 2H),3.43 (br. s., 2H), 2.44 (d, J=7.9 Hz, 1H), 2.26-2.01 (m, 4H), 1.73-1.19(m, 10H), 1.12-0.94 (m, 4H), 0.82 (d, J=7.1 Hz, 3H), 0.65 (d, J=7.1 Hz,3H). MS (ESI): mass calcd. for C₃₀H₄₃BClNO₇ 575.3, m/z found 540.4[M+H]⁺. HPLC: 96.1% (220 nm), 91.0% (weak absorption at 254 nm).

13.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-((dimethylamino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2oxaborol-6-yl)oxy)acetateHydrochloride

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatehydrochloride salt (125.0 mg, 231.7 umol, 1.0 eq.) in CH₃CN (10.0 mL)was added formaldehyde (188.1 mg, 2.3 mmol, 172.5 uL, 37% purity, 10.0eq.), sodium cyanoboranuide (21.8 mg, 347.6 umol, 1.5 eq.) and AcOH (1.4mg, 23.2 umol, 1.3 uL, 0.1 eq). The mixture was stirred at 25° C. for 6hours. HPLC and LCMS indicated the reaction was completed. The reactionmixture was concentrated under reduced pressure to remove CH₃CN. Theresidue purified by pre-HPLC (column: Luna C18 100×30 mm, 5 μm; liquidphase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 20%-50%, 12 min]). Freeze-dryafter added two drops of 2N HCl (aq.),(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-((dimethylamino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatehydrochloride (80.0 mg, 141.0 umol, 60.8% yield) was obtained as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.52 (br. s., 1H), 7.40 (s, 1H),7.31 (d, J=1.6 Hz, 1H), 6.11 (dd, J=11.2, 18.0 Hz, 1H), 5.61 (d, J=8.0Hz, 1H), 5.13-4.98 (m, 4H), 4.75 (d, J=11.2 Hz, 2H), 4.18 (d, J=4.8 Hz,2H), 3.42 (d, J=5.6 Hz, 1H), 2.73 (s, 6H), 2.42 (s, 1H), 2.26-2.01 (m,4H), 1.72-1.57 (m, 3H), 1.55-1.20 (m, 9H), 1.09-0.95 (m, 4H), 0.82 (d,J=6.4 Hz, 3H), 0.64 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. forC₃₂H₄₆BNO₇ 567.3, m/z found 568.5 [M+H]⁺. HPLC: 98.0% (220 nm), 99.2%(254 nm).

14.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of 4-hydroxy-3-methoxybenzaldehyde (40.0 g, 262.9 mmol,1.0 eq) in DCM (500.0 mL) was added TEA (79.8 g, 788.7 mmol, 3.0 eq) andacetyl chloride (30.9 g, 394.4 mmol, 1.5 eq). The mixture was stirred at20° C. for 0.5 hr. The reaction mixture was quenched by addition water100 mL at 20° C., and then adjusted pH to 5-6 by 4 N HCl, then extractedwith DCM (100 mL×2). The combined organic layers were washed with brine(200 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give 4-formyl-2-methoxyphenyl acetate (53.0 g, crude) as alight brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.97 (s, 1H), 7.61 (d,J=1.3 Hz, 1H), 7.58 (dd, J=1.8, 7.9 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H),3.87 (s, 3H), 2.30 (s, 3H).

To a solution of 4-formyl-2-methoxyphenyl acetate (30.0 g, 154.5 mmol,1.0 eq) in DCM (300.0 mL) was added fuming nitric acid (154.5 mmol, 1.0eq) at −30° C. The mixture was stirred at 20° C. for 15 hrs. Thereaction mixture was quenched by addition water 100 mL at 0° C., andthen diluted with DCM 50 mL and extracted with DCM (50 mL×3). Thecombined organic layers were washed with brine (100 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=30/1 to 10:1) to give4-formyl-2-methoxy-3-nitrophenyl acetate (23.0 g, 96.2 mmol, 62.2%yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.91 (s, 1H), 7.96(d, J=8.5 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 3.87 (s, 3H), 2.41 (s, 3H).

To a solution of FeSO₄.7H₂O (145.3 g, 522.6 mmol, 5.0 eq) in H₂O (500.0mL) was added NH₃*H₂O (109.91 g, 3.14 mol, 120.78 mL, 30.00 eq),followed by 4-formyl-2-methoxy-3-nitrophenyl acetate (25.0 g, 104.5mmol, 1.0 eq), and then the mixture was stirred at 100° C. for 2 hrsunder N₂ atmosphere. LCMS showed the reaction was completed. The mixturewas filtered, then washed with warm water (500 mL), the filtrate wasadjusted pH to 4-5 by H₂SO₄, then extracted with EtOAc (100 mL×3), thecombined organic layers was washed with brine (200 mL×1), dried overNa₂SO₄, filtered, concentrated to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=10/1 to 2:1) to give 2-amino-4-hydroxy-3-methoxybenzaldehyde(7.0 g, 41.8 mmol, 40.1% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 10.16 (s, 1H), 9.73 (s, 1H), 9.59 (s, 1H), 7.15 (d, J=8.5 Hz,1H), 6.80 (br. s., 1H), 6.23 (d, J=9.0 Hz, 1H), 3.66 (s, 3H).

To a solution of 2-amino-4-hydroxy-3-methoxybenzaldehyde (6.5 g, 38.9mmol, 1.0 eq) in HBr (10.0 mL) was added H₂O (100.0 mL) and the mixturewas cooled to 0° C., a cold solution of NaNO₂ (2.7 g, 38.9 mmol, 2.1 mL,1.0 eq) in H₂O (100.0 mL) was dropwise added during 10 mins, then CuBr(11.2 g, 77.8 mmol, 2.4 mL, 2.0 eq) was added to the mixture, afteraddition, the mixture was stirred at 70° C. for 1 hr. The reactionmixture was quenched by addition water 10 mL at 25° C., and then dilutedwith MTBE 20 mL and extracted with MTBE (30 mL×3). The combined organiclayers were washed with brine (50 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give2-bromo-4-hydroxy-3-methoxybenzaldehyde (7.0 g, 30.3 mmol, 77.9% yield)as a brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.06 (s, 1H), 10.05 (s,1H), 7.54 (d, J=8.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 3.77 (s, 3H).

A mixture of 2-bromo-4-hydroxy-3-methoxybenzaldehyde (7.0 g, 30.3 mmol,1.0 eq), BnBr (5.2 g, 30.3 mmol, 3.6 mL, 1.0 eq), K₂CO₃ (8.4 g, 60.6mmol, 2.0 eq) and KI (502.9 mg, 3.0 mmol, 0.1 eq) in DMF (100.0 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 25° C. for 4 hrs under N₂ atmosphere. TLC showed the reactionwas completed. The reaction mixture was quenched by addition water 200mL at 0° C., and then diluted with EtOAc 20 mL and extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine (100mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=30/1 to 10:1) togive 4-(benzyloxy)-2-bromo-3-methoxybenzaldehyde (8.0 g, 24.9 mmol,82.2% yield) was obtained as an off-white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 10.11 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.52-7.47 (m, 2H), 7.43(t, J=7.3 Hz, 2H), 7.40-7.34 (m, 2H), 5.30 (s, 2H), 3.80 (s, 3H).

A mixture of 4-(benzyloxy)-2-bromo-3-methoxybenzaldehyde (800.0 mg, 2.5mmol, 1.0 eq), Pin₂B₂ (3.8 g, 14.9 mmol, 6.0 eq), KOAc (488.9 mg, 4.9mmol, 2.0 eq) and Pd(dppf)Cl₂.CH₂Cl₂ (101.7 mg, 124.5 umol, 0.05 eq) indioxane (30.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 70° C. for 18 hrs under N₂ atmosphere. Thereaction solution was filtered and concentrated to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 5:1) to afford4-(benzyloxy)-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1 g, crude) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.80 (s,1H), 7.51 (d, J=8.4 Hz, 1H), 7.45-7.32 (m, 5H), 7.04 (d, J=7.9 Hz, 1H),5.20 (s, 2H), 3.90 (s, 3H), 1.47 (s, 12H).

To a solution of4-(benzyloxy)-3-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(1.7 g, 4.6 mmol, 1.0 eq) in THF (20.0 mL) was added NaBH₄ (209.7 mg,5.5 mmol, 1.2 eq) and MeOH (500.0 uL). The mixture was stirred at 25° C.for 10 mins. Water was added to the mixture, and then adjusted pH to3-4, THF was removed under reduced pressure, the solid was precipitated,filtered, the solid was washed with water for three times, then washedwith petroleum ether for three times to afford6-(benzyloxy)-7-methoxybenzo[c][1,2]oxaborol-1(3H)-ol (700.0 mg, 2.6mmol, 56.1% yield) as a brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.03(s, 1H), 7.46-7.29 (m, 5H), 7.19 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz,1H), 5.08 (s, 2H), 4.88 (s, 2H), 3.93 (s, 3H)

To a solution of 6-(benzyloxy)-7-methoxybenzo[c][1,2]oxaborol-1 (3H)-ol(700.0 mg, 2.6 mmol, 1.0 eq) in EtOAc (20.0 mL) was added Pd/C (10%, 1g) under N₂ atmosphere. The suspension was degassed and purged with H₂for 3 times. The mixture was stirred under H₂ (50 Psi) at 25° C. for 2hrs. The reaction solution was filtered and the filtrate wasconcentrated to give 7-methoxybenzo[c][1,2]oxaborole-1,6(3H)-diol (420.0mg, 2.3 mmol, 90.1% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ8.97 (s, 1H), 8.68 (s, 1H), 6.95-6.91 (m, 1H), 6.83 (d, J=8.0 Hz, 1H),4.85 (s, 2H), 3.90 (s, 3H).

A mixture of 7-methoxybenzo[c][1,2]oxaborole-1,6(3H)-diol (150.0 mg,833.5 umol, 1.0 eq), pleuromutilintosylate (887.9 mg, 1.7 mmol, 2.0 eq),Na₂CO₃ (132.5 mg, 1.2 mmol, 1.5 eq), KI (69.2 mg, 416.7 umol, 0.5 eq) inDMSO (20.0 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 30° C. for 24 hrs under N₂ atmosphere. Water (100mL) was added to the mixture, then adjusted pH to 4-5, the solid wasprecipitated, filtered, and washed with water for three times. The solidwas purified by prep-HPLC (column: Luna C18 100×30 mm, 5 μm; liquidphase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 35%-75%, 12 min]). MeCN wasremoved under reduced pressure. The residue was dried underfreeze-drying to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (200.0 mg, 370.1 umol, 44.4% yield) as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.20-8.94 (m, 1H), 7.03 (d, J=8.4 Hz,1H), 6.91 (d, J=8.4 Hz, 1H), 6.12 (dd, J=11.5, 17.6 Hz, 1H), 5.61 (d,J=8.4 Hz, 1H), 5.10-5.00 (m, 2H), 4.89 (s, 2H), 4.74-4.60 (m, 2H), 3.93(s, 3H), 3.42 (d, J=6.2 Hz, 1H), 2.41 (br. s., 1H), 2.24-1.99 (m, 4H),1.71-1.20 (m, 11H), 1.12-0.94 (m, 4H), 0.82 (d, J=7.1 Hz, 3H), 0.63 (d,J=6.6 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₁BO₈ 540.3, m/z found539.3 [M−1]⁻. HPLC: 100% (220 nm), 100% (254 nm).

15.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-5-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

Ac₂O (24.1 g, 236.6 mmol, 22.1 mL, 1.2 eq) was added to a solution of4-hydroxy-3-methoxy-benzaldehyde (30.0 g, 197.1 mmol, 1.0 eq) and TEA(39.9 g, 394.3 mmol, 54.6 mL, 2.0 eq) in DCM (100.00 mL) at 20° C. Themixture was stirred at 20° C. for 10 hours. TLC showed the reaction wascompleted. The reaction was quenched by addition of water (300 mL), andadjusted pH<5 with 2N HCl, extracted with DCM (100 mL×2). The combinedorganic phase was dried over Na₂SO₄ and concentrated in vacuo to give(4-formyl-2-methoxy-phenyl) acetate (36.0 g, 185.3 mmol, 94.0% yield) ascolorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 9.95 (s, 1H), 7.50-7.47 (m,2H), 7.23 (d, J=8.0 Hz, 1H), 3.92 (s, 3H), 2.35 (s, 3H).

To the suspension of (4-formyl-2-methoxy-phenyl) acetate (35.0 g, 180.2mmol, 1.0 eq) and KBr (72.2 g, 607.4 mmol, 26.2 mL, 3.3 eq) in H₂O(600.0 mL) was added Br₂ (31.9 g, 200.0 mmol, 10.3 mL, 1.1 eq) dropwise.The reaction mixture was stirred for 10 hours at 20° C. The mixture wasfiltered, washed with water and dried. The residue was then added inpetroleum ether (300 mL) and DCM (30 mL) and stirred for 12 hours. Themixture was filtered and washed with petroleum ether and dried to give(5-bromo-4-formyl-2-methoxy-phenyl) acetate (35.0 g, 128.1 mmol, 71.1%yield) as yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.23 (s, 1H), 7.52(s, 1H), 7.36 (s, 1H) 3.89 (s, 3H), 2.34 (s, 3H).

(5-bromo-4-formyl-2-methoxy-phenyl) acetate (10.0 g, 36.6 mmol, 1.0 eq),Pd(dppf)Cl₂ (803.8 mg, 1.10 mmol, 0.03 eq), KOAc (5.3 g, 54.9 mmol, 1.5eq) and Pin₂B₂ (27.9 g, 109.8 mmol, 3.0 eq) in dioxane (150.0 mL) werestirred at 70° C. under N₂ atmosphere for 12 hours. The mixture wasfiltered and concentrated in vacuo. The crude product was purified byflash column chromatography (petroleum ether/EtOAc=3/1) to give[4-formyl-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] acetate (7.6 g, 23.7 mmol,64.8% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.68 (s, 1H),7.63 (s, 1H), 7.62 (s, 1H) 3.92 (s, 3H), 2.33 (s, 3H), 1.37 (s, 12H).

MeOH (5.00 mL) was added to a solution of [4-formyl-2-methoxy-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl] acetate (7.6 g, 23.7mmol, 1.0 eq) and NaBH₄ (1.3 g, 35.6 mmol, 1.5 eq) in THF (100.0 mL) at20° C. The mixture was stirred for 12 hours. The reaction was quenchedby addition of water 50 mL and adjusted to pH<4 with 2N HCl aq.solution. The mixture was extracted with EtOAc (50 mL×3). The combinedorganic phase was dried over Na₂SO₄ and concentrated in vacuo to give(1-hydroxy-5-methoxy-3H-2,1-benzoxaborol-6-yl) acetate (4.5 g, crude) asyellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (s, 1H), 7.16 (s, 1H), 4.94(s, 2H), 3.79 (s, 3H), 2.26 (s, 3H).

NaOH (1.3 g, 33.7 mmol, 1.5 eq) was added to a solution of(1-hydroxy-5-methoxy-3H-2, 1-benzoxaborol-6-yl) acetate (5.0 g, 22.5mmol, 1.00 eq) in MeOH (15.0 mL) and H₂O (30.0 mL). The mixture wasstirred at 20° C. for 3 hours. HPLC showed the reaction was completely.The reaction was quenched by addition of water (50 mL) and treated with2 N HCl till pH<3. The mixture was extracted with EtOAc (50 mL×3), thecombined organic phase was dried over Na₂SO₄ and concentrated in vacuoto give 1-hydroxy-5-methoxy-3H-2, 1-benzoxaborol-6-ol (1.2 g, 6.67 mmol,29.6% yield) as yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.77 (s, 1H),7.07 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 3.76 (s, 3H).

K₂CO₃ (306.8 mg, 2.2 mmol, 2.0 eq) was added to a solution of1-hydroxy-5-methoxy-3H-2,1-benzoxaborol-6-ol (200.0 mg, 1.11 mmol, 1.0eq) and [(12R,13R,14R,15S,16R,19S,20R,21S)-15-hydroxy-12,13,19,20-tetramethyl-17-oxo-19-vinyl-14-tricyclotetradecanyl]2-iodoacetate(542.1 mg, 1.11 mmol, 1.0 eq) in DMSO (10.0 mL). The mixture was stirredat 50° C. for 3 hours. The reaction was quenched by addition of water(50 mL) and treated with 2N HCl till pH<4. White solid was filtered togive crude product. The crude product was purified by prep-HPLC (column:Luna C18 100×30×5 μm; mobile phase: [water (0.1% TFA)-ACN]; B %:40%-70%, 10 min) to give[(21R,22R,23R,24S,25R,28S,29R,30S)-24-hydroxy-21,22,28,29-tetramethyl-26-oxo-28-vinyl-23-tricyclotetradecanyl]-2-[(1-hydroxy-5-methoxy-3H-2,1-benzoxaborol-6-yl)oxy]acetate (86.0 mg, 159.1 umol, 14.3% yield) as white solid. ¹H NMR(DMSO-d₆ 400 MHz) δ 7.11 (s, 1H), 7.02 (s, 1H), 6.09 (dd, J=11.2, 17.6Hz, 1H), 5.58 (d, J=8.4 Hz, 1H), 5.02 (dd, J=17.6, 30.0 Hz, 2H), 4.87(s, 2H), 4.65 (m, 2H), 3.79 (s, 3H), 3.40 (d, J=5.6 Hz, 1H), 2.40 (s,1H), 2.19-2.02 (m, 4H), 1.67-1.60 (m, 2H), 1.35-1.29 (m, 8H), 1.03-1.00(m, 4H), 0.81 (d, J=6.8 Hz, 3H), 0.61 (d, J=6.8 Hz, 3H). MS (ESI): masscalcd. for C₃₀H₄₁BO₈ 540.29, m/z found 539.1 [M−H]⁻. HPLC: 99.8% (220nm), 99.6% (254 nm).

16.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-cyano-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of 2-bromo-4-fluoro-1-methylbenzene (38.5 g, 203.7 mmol,1.0 eq) in THF (1.0 L) was added LDA (2 M, 122.2 mL, 1.2 eq) at −78° C.,the mixture was stirred at −78° C. for 1.5 hours, then ethyl formate(45.3 g, 611.1 mmol, 49.2 mL, 3.0 eq) was added to the mixture at −78°C. The mixture was stirred at −78° C. for 5 min. TLC showed the reactionwas completed. The reaction mixture was quenched by addition water (500mL) at −70° C., and then diluted with EtOAc 100 mL and extracted withEtOAc (500 mL×2). The combined organic layers were washed with brine(1000 mL×1), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatograph (SiO₂,petroleum ether/ethyl acetate=I/O to 10/1) to give2-bromo-6-fluoro-3-methylbenzaldehyde (34.0 g, 156.7 mmol 76.9% yield)was obtained as brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 10.40 (s, 1H), 7.43(dd, J=5.6, 8.4 Hz, 1H), 7.05 (t, J=9.2 Hz, 1H), 2.56-2.37 (m, 3H).

To a solution of 2-bromo-6-fluoro-3-methylbenzaldehyde (29.0 g, 133.6mmol, 1.0 eq) in MeOH (500.0 mL) was added NaOMe (28.9 g, 534.5 mmol,4.0 eq). The mixture was stirred at 70° C. for 5 hours. TLC showed a newspot was formed. The reaction mixture was quenched by addition water(500 mL) at 25° C., and then diluted with EtOAc 100 mL and extractedwith EtOAc (500 mL×2). The combined organic layers were washed withbrine (500 mL×1), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give 2-bromo-6-methoxy-3-methylbenzaldehyde (36.00 gcrude) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.41 (s, 1H), 7.34(d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 2.38 (s, 3H).

To a solution of 2-bromo-6-methoxy-3-methylbenzaldehyde (36.0 g, 157.2mmol, 1.0 eq) in DCM (500.0 mL) was added BBr₃ (78.7 g, 314.3 mmol, 30.3mL, 2.0 eq). The mixture was stirred at −78° C. for 0.5 hour. Thereaction mixture was quenched by addition water (100 mL) at 25° C., andthen diluted with DCM 200 mL and extracted with DCM (200 mL×2). Thecombined organic layers were washed with brine (500 mL×1), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, petroleum ether/ethylacetate=100/1 to 1/1) to give 2-bromo-6-hydroxy-3-methylbenzaldehyde(27.0 g, 125.6 mmol, 79.89% yield) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 12.00 (s, 1H), 10.43 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 6.87 (d,J=8.4 Hz, 1H), 2.39 (s, 3H).

To a solution of 2-bromo-6-hydroxy-3-methylbenzaldehyde (16.0 g, 74.4mmol, 1.0 eq) in DCM (200.0 mL) was added MOMCl (9.0 g, 111.6 mmol, 8.5mL, 1.5 eq) and DIEA (19.2 g, 148.8 mmol, 26.0 mL, 2.0 eq). The mixturewas stirred at 0° C. for 15 hours. TLC showed the reaction wascompleted. The reaction mixture was quenched by addition water (500 mL)at 25° C., and then diluted with DCM 200 mL and extracted with DCM (200mL×2). The combined organic layers were washed with brine (500 mL×2),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=I/O to 5/1). To give2-bromo-6-(methoxymethoxy)-3-methylbenzaldehyde (8.0 g, 30.9 mmol, 41.5%yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.42 (s, 1H), 7.33(d, J=8.4 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 5.23 (s, 2H), 3.50 (s, 3H),2.40 (s, 3H).

To a solution of 2-bromo-6-(methoxymethoxy)-3-methylbenzaldehyde (23.5g, 90.7 mmol, 1.0 eq) in THF (200.0 mL) and H₂O (50.0 mL) was added KOAc(17.8 g, 181.4 mmol, 2.0 eq) and NH₂OH.HCl (9.5 g, 136.1 mmol, 1.5 eq).The mixture was stirred at 25° C. for 0.5 hour. TLC showed the reactionwas completed. The reaction mixture was quenched by addition water (200mL) at 0° C., and then diluted with EtOAc 50 mL and extracted with EtOAc(100 mL×2). The combined organic layers were washed with brine (300mL×1), dried over Na₂SO₄, filtered and concentrated under reducedpressure to (E)-2-bromo-6-(methoxymethoxy)-3-methylbenzaldehyde oxime(25.0 g, crude) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 11.36 (s,1H), 8.07 (s, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.13(s, 2H), 3.32 (s, 3H), 2.28 (s, 3H)

To a solution of (E)-2-bromo-6-(methoxymethoxy)-3-methylbenzaldehydeoxime (25.0 g, 91.2 mmol, 1.0 eq) in THF (300.0 mL) was added TEA (27.7g, 273.6 mmol, 37.9 mL, 3.0 eq) and TFAA (38.3 g, 182.4 mmol, 25.4 mL,2.0 eq). The mixture was stirred at 25° C. for 1 hour. TLC showed thereaction was completed. The reaction mixture was quenched by additionwater (100 mL) at 0° C., and then diluted with EtOAc 50 mL and extractedwith EtOAc (100 mL×2). The combined organic layers were washed withNaHCO₃ (100 mL×1), then brine (200 mL×1), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give2-bromo-6-(methoxymethoxy)-3-methylbenzonitrile (23.00 g, crude) as ayellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 11.36 (s, 1H), 8.07 (s, 1H),7.28 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.21-5.09 (m, 2H), 3.32(s, 3H), 2.28 (s, 3H)

To a solution of 2-bromo-6-(methoxymethoxy)-3-methylbenzonitrile (2.3 g,9.0 mmol, 1.0 eq) in CCl₄ (150.0 mL) was added NBS (2.4 g, 13.5 mmol,1.5 eq) and BPO (217.5 mg, 898.0 umol, 0.1 eq). The mixture was stirredat 80° C. for 15 hours. TLC showed the reaction was completed. Thereaction mixture was quenched by addition water (100 mL) at 25° C., andthen diluted with DCM (100 mL) and extracted with DCM (100 mL×2). Thecombined organic layers were washed with brine (200 mL×1), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give2-bromo-3-(bromomethyl)-6-(methoxymethoxy) benzonitrile (3.0 g, crude)as a brown solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (d, J=8.8 Hz, 1H), 7.21(d, J=8.8 Hz, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 3.53 (s, 3H).

To a solution of 2-bromo-3-(bromomethyl)-6-(methoxymethoxy)benzonitrile(3.0 g, 9.0 mmol, 1.0 eq) in DMF (30.0 mL) was added KOAc (2.6 g, 26.9mmol, 3.0 eq). The mixture was stirred at 25° C. for 0.5 hour. TLCshowed a new spot was formed. The reaction mixture was quenched byaddition water (30 ml) at 25° C., and then diluted with EtOAc 10 mL andextracted with EtOAc (10 mL×2). The combined organic layers were washedwith brine (20 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 10/1) togive 2-bromo-3-cyano-4-(methoxymethoxy)benzyl acetate (2.0 g, 6.4 mmol,71.0% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (d, J=8.4Hz, 1H), 7.22 (d, J=9.2 Hz, 1H), 5.31 (s, 2H), 5.16 (s, 2H), 3.53 (s,3H), 2.13 (s, 3H).

A mixture of 2-bromo-3-cyano-4-(methoxymethoxy)benzyl acetate (1.3 g,4.1 mmol, 1.0 eq), Pd (PPh₃)₂Cl₂ (87.2 mg, 124.2 umol, 0.03 eq), KOAc(609.2 mg, 6.2 mmol, 1.5 eq) and Pin₂B₂ (3.2 g, 12.4 mmol, 3.0 eq) indioxane (100.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 70° C. for 15 hours under N₂ atmosphere. HPLCand LCMS showed the reaction was completed. The reaction mixture wasquenched by addition water (50 mL) at 25° C., and then diluted withEtOAc 10 mL and extracted with EtOAc (50 mL×2). The combined organiclayers were washed with brine (50 mL×1), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give3-cyano-4-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (1.5 g crude) as a black solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.50(d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 5.15 (s, 2H),3.79 (s, 3H), 3.52 (s, 3H), 1.42 (s, 12H).

To a solution of3-cyano-4-(methoxymethoxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (1.3 g, 3.6 mmol, 1.0 eq) in MeOH (50.0 mL) and H₂O(100.0 mL) was added NaOH (287.9 mg, 7.2 mmol, 2.0 eq). The mixture wasstirred at 25° C. for 12 hours. HPLC and LCMS showed the reaction wascompletely. The reaction mixture was quenched by addition water (100mL), then the mixture was adjusted pH about 6 at 25° C., and thendiluted with EtOAc 100 mL and extracted with EtOAc (100 mL×2). Thecombined organic layers were washed with brine (200 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (column: Luna C8 100×30×5 μm; mobile phase:[water (0.1% TFA)-ACN]; B %: 15%-40%, 12 min) to give1-hydroxy-6-(methoxymethoxy)-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile(120.0 mg, 548.0 umol, 15.2% yield) as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.51 (d, J=8.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 5.32 (s, 2H),5.07 (s, 2H), 3.55 (s, 3H).

To a solution of1-hydroxy-6-(methoxymethoxy)-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile(80.0 mg, 365.3 umol, 1.0 eq) in DCM (20.0 mL) was added CF₃COOH (124.95mg, 1.1 mmol, 81.1 uL, 3.0 eq). The mixture was stirred at 25° C. for 12hours. HPLC showed the reaction was completed. The reaction wasconcentrated to give1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile (80.0 mg,crude) as a yellow solid, which was used directly for next step.

To a solution of1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-7-carbonitrile (90.0 mg,514.4 umol, 1.0 eq) and [(12R,13R,14R,15S, 16R,19S,20R,21S)-15-hydroxy-12,13,19,20-tetramethyl-17-oxo-19-vinyl-14-tricyclotetradecanyl]2-iodoacetate(276.4 mg, 565.9 umol, 1.1 eq) in DMSO (150 mL) was added K₂CO₃ (106.7mg, 771.6 umol, 1.5 eq). The mixture was stirred at 40° C. for 15 hours.HPLC showed the reaction was completed. The reaction mixture wasquenched by addition of ice (20 g) and water (50 mL), and was adjustedto pH=7. The solid was filtered, washed by water for 3 times andconcentrated under reduced pressure. The residue was purified byprep-HPLC ([water (0.1% TFA)-ACN]; B %: 37%-67%, 12 min) to give (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-cyano-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(70.0 mg, 130.7 umol, 25.4% yield) as a white solid. ¹H NMR (DMSO-d₆,400 MHz) δ 7.65-7.56 (m, 1H), 7.31-7.22 (m, 1H), 6.10 (dd, J=11.2, 17.7Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.12-4.92 (m, 6H), 3.41 (d, J=6.0 Hz,1H), 2.41 (br. s., 1H), 2.25-1.98 (m, 4H), 1.71-1.19 (m, 11H), 1.10-0.93(m, 4H), 0.81 (d, J=6.8 Hz, 3H), 0.65 (d, J=6.8 Hz, 3H). MS (ESI): masscalcd for C₃₀H₃₈BNO₇ 535.44, m/z found 552.1 [M+H₂O−H]⁻. HPLC: 99.13%(220 nm), 100% (254 nm).

17. tert-butyl4-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)piperidine-1-carboxylate18.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-4-(piperidin-4-yl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

A solution of 3,5-dimethoxyaniline (4.74 g, 30 mmol) in water (50 mL)was cooled in ice-salt bath, and a thermal probe inserted to monitorinternal temperature. To this suspension was slowly added 98% sulphuricacid (8.55 g, 82.8 mmol). A solution of NaNO₂ (2.45 g, 35.1 mmol) in 10mL water was added slowly via syringe over a period of 15 minutes. Thedeep red solution was stirred at −5 to −3° C. for 30 minutes, then 25 mLof Et₂O was added. A solution of KI (15.3 g, 90.9 mmol) in 15 mL waterwas added via syringe over 30 minutes at such a rate that kept internaltemperature around 1-2° C. Following complete addition, the reactionmixture was stirred for a further 3 hour at 0° C. The crude was thenpoured into a reparatory funnel, washed with saturated Na₂S₂O₃ solution(100 mL), and the aqueous washing extracted with EA (3×200 mL). Theorganics were pooled, washed successively with saturated Na₂S₂O₃solution (100 mL) and brine (100 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (eluent: PE/EA=10:1) to give1-iodo-3,5-dimethoxybenzene (4.00 g, yield 50.5%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 6.88 (s, 2H), 6.50 (s, 1H), 3.73 (s, 6H).

To a stirred solution of 1-iodo-3,5-dimethoxybenzene (17.4 g, 66.0 mmol)in DMF (112 mL) was carefully added dropwise POCl₃ (27.2 g, 176 mmol)over 30 min 0° C. The mixture obtained was heated to 100° C. for 24 h,then poured onto ice and left overnight. The precipitate was filteredand washed with water (4×500 mL) and the aqueous solution was extractedwith DCM (4×300 mL). The combined organic layers were dried over Na₂SO₄,concentrated in vacuo. The crude residue was purified by columnchromatography (eluent: PE/EA=10:1 to 3:1) to give2-iodo-4,6-dimethoxybenzaldehyde (7.00 g, yield 36.4%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 10.14 (s, 1H), 7.13 (s, 1H), 6.48 (s,1H), 3.89 (s, 1H), 3.87 (s, 1H).

To a solution of 2-iodo-4,6-dimethoxybenzaldehyde (7.00 g, 24.0 mmol) inDCM (40 mL) was added dropwise a 1 M solution of BBr₃ in DCM (96 mL)over 15 min at 25° C. under N₂. The orange solution was stirred at rtfor 4 h, quenched with water (300 mL), and extracted with DCM (3×300mL). The combined extracts were washed with brine (200 mL), dried withanhydrous Na₂SO₄ and concentrated in vacuo to give the residue which waspurified by column chromatography (eluent: PE/EA=10:1 to 1:1) to give2,4-dihydroxy-6-iodobenzaldehyde (5.25 g, yield 82.9%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): δ 12.49 (s, 1H), 9.86 (s, 1H), 7.02 (s,1H), 6.38 (s, 1H), 3.89-3.85 (m, 1H).

A stirring mixture of 2,4-dihydroxy-6-iodobenzaldehyde (5.25 g, 19.1mmol), NaHCO₃ (1.84 g, 21.8 mmol) and KI (641 mg, 3.82 mmol) in MeCN(100 mL) was slowly warmed to 60° C. At this time, BnBr (3.98 g, 23.06mmol) was added and the mixture was warmed to 80° C. After refluxingovernight, KHCO₃ (965 mg, 9.54 mmol) was added and the mixture wasstirred for additional 5 hours. The mixture was then cooled to roomtemperature and concentrated by rotary evaporation. The residue wasquenched with 10% aq. HCl (10 mL) and extracted with EA (3×300 mL). Thecombined organic extracts were washed with brine (100 mL), dried withanhydrous Na₂SO₄, filtered, and concentrated in vacuo to give theresidue which was purified by column chromatography (eluent: PE/EA=10:1to 8:1) to give 4-(benzyloxy)-2-hydroxy-6-iodobenzaldehyde (5.60 g,yield 92.8%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.22 (s,1H), 9.83 (s, 1H), 7.46-7.34 (m, 5H), 7.23 (s, 1H), 6.64 (s, 1H), 5.22(s, 2H).

To a solution of 4-(benzyloxy)-2-hydroxy-6-iodobenzaldehyde (4.26 g,11.8 mmol) in dioxane (120 mL) were added successively Pd(PPh₃)Cl₂ (664mg, 0.994 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(4.60 g, 14.2 mmol), and Na₂CO₃ (3.79 g, 35.4 mmol) at RT. Afterstirring overnight at 110° C., Solvent was evaporated and the resultingoil was diluted with water (300 mL). The mixture was extracted with EA(3×300 mL). The combined organic extracts were washed with brine (300mL), dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo togive the residue which was purified by column chromatography (eluent:PE/EA=6:1) to give tert-butyl4-(5-(benzyloxy)-2-formyl-3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(4.51 g, yield 93.4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ12.15 (s, 1H), 9.85 (s, 1H), 7.47-7.35 (m, 5H), 6.52 (s, 2H), 5.69 (s,1H), 5.20 (s, 2H), 3.98 (s, 2H), 3.57-3.53 (m, 2H), 2.37 (s, 2H), 1.43(s, 9H), 1.40 (s, 2H).

To a mixture of tert-butyl4-(5-(benzyloxy)-2-formyl-3-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate(4.69 g, 11.2 mmol), TEA (2.30 g, 22.5 mmol) and DMAP (2.10 g, 16.9mmol) in DCM (60 mL) was added dropwise Tf₂O (4.85 g, 16.9 mmol) at 0°C. under nitrogen atmosphere. The reaction mixture was stirred overnightat room temperature and diluted with ice water (50 g) and separated. Theaqueous layer was extracted with DCM (3×50 mL). The combined organiclayer was washed sequentially with water (50 mL) and brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to give the residue whichwas purified by column chromatography (eluent: PE/EA=5:1-3:1) to givetert-butyl4-(5-(benzyloxy)-2-formyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(6.08 g, yield 59.1%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.86 (s, 1H), 7.49-7.37 (m, 5H), 7.25 (s, 1H), 7.07 (s, 1H), 5.68 (s,1H), 5.29 (s, 2H), 4.02 (s, 2H), 3.60-3.57 (m, 2H), 2.46 (s, 2H), 1.44(s, 9H).

A mixture of tert-butyl4-(5-(benzyloxy)-2-formyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(3.42 g, 6.19 mmol), Bis(pinacolato)diboron (3.21 g, 12.4 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (1.03 g, 1.24 mmol), KOAc (2.76 g, 27.8 mmol) in1,4-dioxane (100 mL) was degassed with N₂ for 10 minutes. The reactionmixture was stirred at 70-80° C. for 16 h. TLC (EtOAc/petroleumether=1:1) indicated the reaction was completed. The reaction mixturewas poured into water (400 mL) and extracted with EtOAc (3×200 mL). Thecombined organic phases were dried over anhydrous Na₂SO₄, andconcentrated in vacuo to give the residue which was purified byprep-HPLC to give tert-butyl4-(5-(benzyloxy)-2-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(750 mg, yield 23.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.88 (s, 1H), 7.50-7.35 (m, 5H), 7.02 (s, 1H), 6.96 (s, 1H), 5.67 (s,1H), 5.22 (s, 2H), 4.00 (s, 2H), 3.59-3.58 (m, 2H), 2.44 (s, 2H), 1.44(s, 9H), 1.32 (s, 12H).

To a solution of tert-butyl4-(5-(benzyloxy)-2-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(750 mg) in EtOH (25 mL) was added NaBH₄ (204 mg, 5.20 mmol) in smallportions at 0° C. under nitrogen atmosphere. The reaction mixture wasstirred at rt for 4 h. To the reaction mixture was added dropwise 2 NHCl/water (30 mL) at 0° C. The reaction mixture was stirred overnight atrt and evaporated. The resulting oil was diluted with water (100 mL).The mixture was extracted with EA (3×500 mL). The combined organicextracts were washed with brine (100 mL), dried with anhydrous Na₂SO₄,filtered, and concentrated in vacuo to give the residue which waspurified by column chromatography (eluent: PE/EA=5:1) to give tert-butyl4-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate(396 mg, yield 72.4%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.16 (s, 1H), 7.47-7.33 (m, 5H), 7.25 (s, 1H), 7.04 (s, 1H), 5.87 (s,1H), 5.14 (s, 2H), 5.00 (s, 2H), 4.12 (s, 2H), 3.52-3.50 (m, 2H), 2.40(s, 2H), 1.43 (s, 9H).

To a solution of tert-butyl4-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate(290 mg, 0.689 mmol) in MeOH (20 mL)) at rt under H₂ was added 10% Pd/C(100 mg). The reaction mixture was stirred at rt overnight. The mixturewas filtered and concentrated under reduced pressure. The residueobtained was purified by prep-TLC (PE/EA=2/1) to get tert-butyl4-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)piperidine-1-carboxylate(150 mg, yield 65.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.22 (s, 1H), 9.01 (s, 1H), 6.95 (s, 1H), 6.70 (s, 1H), 4.94 (s, 1H),4.07-4.03 (m, 2H), 2.83-2.74 (m, 2H), 2.59-2.56 (m, 1H), 1.67 (d, J=12.4Hz, 2H), 1.42 (s, 9H).

The mixture of tert-butyl4-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)piperidine-1-carboxylate(100 mg, 0.294 mmol), Iodo-pleuromutilin (220 mg, 0.441 mmol) and K₂CO₃(103 mg, 0.735 mmol) in DMF (4 mL) was stirred at rt overnight, filteredand concentrated under reduced pressure. The residue obtained waspurified by prep-HPLC to give tert-butyl4-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)piperidine-1-carboxylate(130 mg, yield 65.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.16 (s, 1H), 7.15 (s, 1H), 6.85 (s, 1H), 6.16-6.06 (m, 1H), 5.59 (d,J=11.6 Hz, 2H), 5.10-4.98 (m, 4H), 4.73 (s, 2H), 4.52 (d, J=8.0 Hz, 1H),4.09-4.04 (m, 2H), 3.42 (s, 1H), 2.78-2.42 (m, 4H), 2.20-1.98 (m, 4H),1.78-1.25 (m, 22H), 1.11-0.95 (m, 5H), 0.78 (d, J=11.6 Hz, 3H), 0.66 (d,J=11.6 Hz, 3H).

To the solution of tert-butyl4-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)piperidine-1-carboxylate(580 mg, 0.830 mmol) in EA (15 mL) was added dropwise 2 N HCl/EA (15 mL)at 0° C. The reaction mixture was stirred for 3 h at rt and filtered.The white solid obtained was washed with EA (3×50 mL) and dried in vacuoto give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-4-(piperidin-4-yl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(470 mg, 94.7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s,1H), 8.76 (s, 1H), 8.53 (s, 1H), 7.08 (d, J=2.0 Hz, 2H), 6.84 (d, J=2.0Hz, 2H), 6.13-6.06 (m, 1H), 5.59 (d, J=8.4 Hz, 1H), 5.10-4.98 (m, 4H),4.76-4.54 (m, 3H), 3.44-3.41 (m, 1H), 3.02-2.75 (m, 4H), 2.41 (s, 1H),2.20-2.03 (m, 4H), 1.86 (s, 4H), 1.68-1.22 (m, 11H), 1.03-0.97 (m, 5H),0.82 (d, J=6.8 Hz, 3H), 0.65 (d, J=1.6 Hz, 3H).

19.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

2-bromo-4-fluorobenzaldehyde (3 g, 14.7 mmol), benzyl alcohol (1.6 g,14.7 mmol) and cesium carbonate (7.2 g, 22.1 mmol) in DMF (15 mL) wereheated to 50-60° C. overnight. TLC shown 2-bromo-4-fluorobenzaldehydeconsumed. Water (30 mL) was added, the aqueous layer was extracted withEtOAc (20 mL) twice. The combined organic layers were washed with brine,dried over Na₂SO₄, and concentrated to give crude product, which waspurified by flash chromatography (EtOAc/petroleum ether, 1:10) to give4-(benzyloxy)-2-bromobenzaldehyde (2.3 g, yield 80.9%). ¹H NMR (CDCl₃,400 MHz) δ 10.23 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.47-7.30 (m, 5H),7.24 (d, J=2.4 Hz, 1H), 7.02 (dd, J=8.8, 2.4 Hz, 1H), 5.14 (s, 2H).

Methyl magnesium bromide solution (4.7 mL, 15.7 mmol, 3M in THF) wasadded to a cooled solution of 4-(benzyloxy)-2-bromobenzaldehyde (2.4 g,8.2 mmol) in THF (50 mL) at −5° C. The mixture was stirred at roomtemperature for 2 hrs. Water (50 mL) was added, the aqueous layer wasextracted with EtOAc (50 mL) twice. The combined organic layers werewashed with brine, dried over Na₂SO₄, and concentrated to give crudeproduct, which was purified by flash chromatography (EtOAc/petroleumether, 1:5) to give 1-(4-(benzyloxy)-2-bromophenyl)ethanol (1.8 g, yield72.1%). ¹H NMR (CDCl₃, 400 MHz) δ 7.49 (d, J=8.8 Hz, 1H), 7.47-7.31 (m,5H), 7.17 (d, J=2.8 Hz, 1H), 6.97 (dd, J=8.6, 2.8 Hz, 1H), 5.21 (q,J=6.4 Hz, 1H), 5.05 (s, 2H), 1.48 (d, J=6.4 Hz, 3H).

A mixture of 1-(4-(benzyloxy)-2-bromophenyl) ethanol (1.8 g, 5.8 mmol),Pd(dppf)Cl₂ (0.21 g), potassium acetate (1.7 g, 17.5 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.2 g, 8.8mmol) in dioxane (15 mL) was bubbled with nitrogen gas for 10 mins thenstirred at 80° C. overnight under nitrogen atmosphere. After thereaction was completed, the mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by flashchromatography (EtOAc/petroleum ether, 1:20˜1:2) to give6-(benzyloxy)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.5 g, yield 30%)as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.05 (s, 1H), 7.48-7.29 (m,7H), 7.01-6.94 (m, 1H), 5.16-5.12 (m, 3H), 1.36 (d, J=8.4 Hz, 3H).

6-(benzyloxy)-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.8 g, 3.1 mmol)was dissolved in EtOAc (80 mL). To this solution under nitrogen wasadded Pd/C (0.4 g). The reaction mixture was vacuumed and backfilledhydrogen for 3 times, then hydrogenated at room temperature, 50 psi for4 hrs. After filtration and rotary evaporation, the residue was purifiedby Pre-HPLC to give 3-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.2 g,38% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.28 (s, 1H),8.95 (br. s., 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.86(dd, J=8.4, 2.4 Hz, 1H), 5.10 (q, J=6.4 Hz, 1H), 1.34 (d, J=6.4 Hz, 3H).MS (ESI): mass calcd. for C₈H₉BO₃ 164.1, m/z found 163.1 [M−1]⁻. HPLC:99.8% (220 nm), 100% (254 nm).

A mixture of Tos-pleuromutilin (0.32 g, 0.6 mmol),3-methylbenzo[c][1,2]oxaborole-1,6(3H)-diol (0.1 g, 0.6 mmol) and K₂CO₃(0.25 g, 1.8 mmol) in 20 mL DMF was heated at 50° C. overnight. Mainpeak on LCMS was desired product. Water (50 mL) was added and themixture was adjust to pH=4 with 2N aqueous HCl. White solid precipitatedand the mixture was filtered, the crude product was purified byprep-HPLC (column: Luna C18 100×30 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.1% v/v; B-ACN] B %: 40%-70%, 20 min]) to give desired(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(171 mg, yield 53%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.00 (s,1H), 7.28 (d, J=9.2 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.02 (d, J=8.0 Hz,1H), 6.09 (dd, J=17.6, 11.4 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.15-4.98(m, 3H), 4.72-4.62 (m, 2H), 4.51 (d, J=6.0 Hz, 1H), 3.40 (m, 1H), 2.40(s, 1H), 2.26-1.98 (m, 4H), 1.67-1.26 (m, 14H), 1.07-1.01 (m, 3H), 0.81(d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H). MS (ESI): mass calcd. forC₃₀H₄₁BO₇ 524.3, m/z found 523.2 [M−1]⁻. HPLC: 93.3% (220 nm), 100% (254nm).

20.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

1-(2-bromo-4-hydroxyphenyl)ethanone (3.5 g, 16.3 mmol), benzyl bromide(3.3 g, 16.3 mmol) and potassium carbonate (3.5 g, 24.4 mmol) in DMF (15mL) were stirred at room temperature overnight. Water (50 mL) was added,the aqueous layer was extracted with EtOAc three times. The combinedorganic layers were dried over Na₂SO₄, and concentrated. Crude productwas purified by flash chromatography to give1-(4-(benzyloxy)-2-bromophenyl)ethanone (4.3 g, yield 86%). ¹H NMR:(DMSO-d₆, 400 MHz) δ 7.59 (d, J=8.5 Hz, 1H), 7.46-7.34 (m, 5H), 7.26 (d,J=2.4 Hz, 1H), 6.95 (dd, J=8.5, 2.4 Hz, 1H), 5.11 (s, 2H), 2.63 (s, 3H).

Methyl magnesium bromide solution (5 mL, 15 mmol, 3M in THF) was addedto a cooled solution of 1-(4-(benzyloxy)-2-bromophenyl)ethanone (2.3 g,7.5 mmol) in THF (50 mL) at −5° C. The mixture was stirred at roomtemperature for 2 hrs. Water (50 mL) was added, the aqueous layer wasextracted with EtOAc (50 mL) twice, the crude product was purified byflash chromatography to give 2-(4-(benzyloxy)-2-bromophenyl)propan-2-ol(2 g, 83% yield). ¹H NMR: (CDCl3, 400 MHz) δ 7.56 (d, J=9.0 Hz, 1H),7.43-7.32 (m, 5H), 7.25 (d, J=2.8 Hz, 1H), 6.90 (dd, J=8.8, 2.8 Hz, 1H),5.05 (s, 1H), 1.73 (s, 6H).

2-(4-(benzyloxy)-2-bromophenyl)propan-2-ol (1.5 g, 4.6 mmol),Pd(dppf)Cl₂ (0.17 g), potassium acetate (1.46 g, 14.9 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.8 g, 7.0mmol) in dioxane (15 mL) was bubbled with nitrogen gas for 10 mins thenstirred at 80° C. overnight under nitrogen atmosphere. After thereaction was completed, the mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by flashchromatography to give6-(benzyloxy)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (0.3 g, yield24%).

6-(benzyloxy)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (0.5 g, 1.8mmol) was dissolved in EtOAc (80 ml). To this solution under nitrogenwas added Pd/C (0.2 g). The reaction mixture was vacuumed and backfilledhydrogen for 3 times, then hydrogenated at room temperature, 50 psi for4 hrs. After filtration and rotary evaporation, the residue was purifiedby Pre-HPLC to give 3, 3-dimethylbenzo[c][1,2]oxaborole-1,6(3H)-diol(0.2 g, 60% yield). ¹H NMR: (DMSO-d₆, 400 MHz) δ 9.26 (s, 1H), 8.88 (br.s., 1H), 7.16 (d, J=8.0 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.83 (dd,J=8.0, 2.4 Hz, 1H), 1.38 (s, 6H). MS (ESI): mass calcd. for C₉H₁₁BO₃178.1, m/z found 177.1 [M−1]⁻. HPLC: 99.2% (220 nm), 93.2% (254 nm).

(3aR, 4R, 5R, 7S, 8S, 9R, 9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (0.12 g, 0.23 mmol), 3,3-dimethylbenzo[c][1,2]oxaborole-1,6(3H)-diol (40 mg, 0.23 mmol) andK₂CO₃ (0.1 g, 0.68 mmol) in 10 mL DMF was heated at 50° C. overnight.Main peak on LCMS was desired product. Water was added and the mixturewas adjust to pH<4 with 2N aqueous HCl. White solid precipitated and themixture was filtered, the crude product was purified by prep-HPLC(column: Luna C18 100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v;B-ACN] B %: 30%-70%, 20 min]) to give desired(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(66 mg, yield 54%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.92 (s,1H), 7.29 (d, J=8.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.00 (dd, J=8.4,2.4 Hz, 1H), 6.09 (dd, J=17.6, 11.2 Hz, 1H), 5.59 (d, J=8.4 Hz, 1H),5.08-4.95 (m, 2H), 4.75-4.61 (m, 2H), 4.51 (d, J=6.0 Hz, 1H), 3.45-3.38(m, 1H), 2.40 (s, 1H), 2.25-1.98 (m, 5H), 1.73-1.55 (m, 3H), 1.52-1.15(m, 12H), 1.08-0.98 (m, 4H), 0.81 (d, J=7.0 Hz, 3H), 0.62 (d, J=6.8 Hz,3H). MS (ESI): mass calcd. for C₃₁H₄₃BO7₃ 538.3, m/z found 537.2 [M−1]⁻.HPLC: 99.3% (220 nm), 100% (254 nm).

21.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetateHydrochloride

Nitromethane (2.7 g, 44.36 mmol) was added to a solution of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(10.0 g, 29.6 mmol) and NaOH (1.2 g, 31.1 mmol) in H₂O (50.0 mL) at 25°C. The mixture was stirred at 25° C. for 1 hour. LCMS showed major asdesired, water (50 mL) was added to the mixture and neutralized by 2NHCl. The mixture was treated with EtOAc (50 mL×3) and purified by flashsilica gel chromatography to give6-(benzyloxy)-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (4.2 g,crude). ¹H NMR (CDCl₃, 400 MHz) δ 8.17 (s, 1H), 7.83 (d, J=8.4 Hz, 2H),7.36 (d, J=8.4 Hz, 2H), 6.23 (dd, J=11.4, 17.6 Hz, 1H), 5.71 (d, J=7.8Hz, 1H), 5.30-5.14 (m, 2H), 5.03 (d, J=6.6 Hz, 1H), 4.49 (s, 2H), 3.08(d, J=13.2 Hz, 1H).

6-(benzyloxy)-3-(nitromethyl)benzo[c][1,2]oxaborol-1 (3H)-ol (4.2 g,14.0 mmol) and Fe (3.9 g, 70.2 mmol) in HCl (10.0 mL) and MeOH (50.0 mL)were heated to reflux for 3 hours. The mixture was cooled to 25° C.,water (50 mL) was added to the mixture, and filtered and dried to give3-(aminomethyl)-6-(benzyloxy)benzo[c][1,2] oxaborol-1(3H)-ol (2.0 g,52.9% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.50 (s, 1H), 8.14 (br. s.,3H), 7.50-7.37 (m, 6H), 7.34 (d, J=7.0 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz,1H), 5.28 (d, J=7.0 Hz, 1H), 5.13 (s, 2H), 3.46 (d, J=14.2 Hz, 1H),2.79-2.69 (m, 1H).

3-(aminomethyl)-6-(benzyloxy)benzo[c][1,2]oxaborol-1 (3H)-ol (2.0 g, 7.4mmol), TEA (2.3 g, 22.3 mmol) and Boc₂O (2.4 g, 11.2 mmol) in DCM (30.0mL) were stirred at 25° C. for 2 hours. The solvent was evaporated. Thecrude product was purified by prep-HPLC to give tert-butyl((6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate (600.0 mg, 21.9% yield).

To a solution of tert-butyl ((6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate (1.0 g, 2.7 mmol)in EtOAc (100.0 mL) was added Pd/C (500.0 mg) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (40 psi) at 25° C. for 2 hours. The reactionmixture was filtered and the filter was concentrated to give tert-butyl((1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl) methyl)carbamate(620.0 mg, 57.4% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ9.34 (s, 1H), 9.07 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.07 (d, J=2.2 Hz,1H), 6.91 (br. s., 1H), 6.85 (dd, J=2.4, 8.2 Hz, 1H), 5.00 (dd, J=4.4,7.1 Hz, 1H), 2.96 (dd, J=6.8, 14.3 Hz, 2H), 1.38-1.34 (s, 9H.).

To a solution of tert-butyl((1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl) methyl)carbamate(250.0 mg, 895.7 umol), pleuromutilintosylate (477.2 mg, 895.7 umol) andK₂CO₃ (371.4 mg, 2.7 mmol) in CH₃CN (10.0 mL) was stirred at 70° C. for12 hours. Water (10 mL) was added to the mixture and filtered to givethe product(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(205.0 mg, 35.8% yield) as yellow solid, which was purified by pre-HPLC.¹H NMR (CDCl₃, 400 MHz) δ 7.28 (br. s., 1H), 7.14-7.07 (m, 2H), 6.48(dd, J=11.0, 16.8 Hz, 1H), 5.86 (d, J=8.4 Hz, 1H), 5.38-5.19 (m, 3H),4.86 (br. s., 1H), 4.61-4.55 (m, 2H), 3.37 (d, J=6.2 Hz, 1H), 2.43-2.05(m, 7H), 1.93-1.09 (m, 20H), 0.97-0.72 (m, 10H).

HCl/EtOAc (4 M, 4.0 mL) was added to a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(200.0 mg, 312.7 umol) in DCM (50.0 mL) at 25° C. for 2 hours. Thesolvent was concentrated and filtered to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(96.0 mg, 52.8% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.47(br. s., 1H), 8.13 (br. s., 3H), 7.44 (d, J=8.4 Hz, 1H), 7.28 (d, J=2.2Hz, 1H), 7.09 (td, J=2.4, 8.5 Hz, 1H), 6.10 (dd, J=11.2, 17.9 Hz, 1H),5.60 (d, J=8.4 Hz, 1H), 5.28 (dd, J=2.6, 9.3 Hz, 1H), 5.12-4.96 (m, 2H),4.80-4.64 (m, 2H), 4.62-4.48 (m, 1H), 3.42 (d, J=5.7 Hz, 2H), 2.78-2.63(m, 1H), 2.42 (br. s., 1H), 2.26-2.00 (m, 4H), 1.73-1.18 (m, 7H), 1.05(s, 2H), 0.89-0.78 (m, 5H), 0.63 (d, J=7.2 Hz, 3H). MS (ESI): masscalcd. for C₃₀H₄₂BNO₇ 539.31, m/z found 540.1 [M+H]⁺. HPLC: 99.2% (220nm), 100.0% (254 nm).

22.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(acetamidomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatehydrochloride (30.0 mg, 52.1 umol, 1.0 eq) and Et₃N (15.8 mg, 156.3umol, 3.0 eq) in DCM (10 mL) was added acetyl chloride (4.1 mg, 52.1umol, 1.0 eq). The mixture was stirred at 25° C. for 6 hours. HPLCindicated reactant was consumed completely. The reaction mixture wasquenched by addition water 30 mL at 0° C., and then extracted with DCM90 mL (30 mL×3). The combined organic layers were washed with brine 150mL (50 mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(acetamidomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(30.0 mg, 51.6 umol, 99.0% yield) as a white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.18 (s, 1H), 8.10 (brs, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.19 (s,1H), 7.03 (dd, J=8.4, 2.4 Hz, 1H), 6.09 (dd, J=17.6, 11.2 Hz, 1H), 5.59(d, J=8.4 Hz, 1H), 5.03-5.11 (m, 2H), 5.00 (d, J=10.8 Hz, 1H), 4.64-4.77(m, 2H), 4.55 (d, J=5.6 Hz, 1H), 3.51 (d, J=13.6 Hz, 1H), 3.41 (brs,1H), 2.96-3.11 (m, 1H), 2.42 (s, 1H), 2.14-2.25 (m, 1H), 2.00-2.12 (m,4H), 1.81 (s, 3H), 1.57-1.72 (m, 2H), 1.34 (s, 3H), 1.22-1.28 (m, 3H),1.04-0.92 (m, 4H), 0.81 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H). MS(ESI): mass calcd. for C₃₂H₄₄BNO₈ 581.5, m/z found 582.3 [M+H]⁺. HPLC:96.0% (220 nm), 92.8% (254 nm).

23.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(methylsulfonamidomethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatehydrochloride (30.0 mg, 52.1 umol, 1.0 eq) and TEA (15.8 mg, 156.3 umol,3.0 eq) in DCM (10 mL) was added MsCl (6.0 mg, 52.1 umol, 1.0 eq). Themixture was stirred at 15° C. for 4 hours. HPLC indicated (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatehydrochloride was consumed completely. The reaction mixture was quenchedby addition H₂O 20 mL at 0° C., and then adjusted PH=5 (aq. HCl, 2 m)and extracted with DCM 60 mL (20 mL×3). The combined organic layers werewashed with brine 30 mL, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified byprep-HPLC (column: Luna C18 150×25 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 33%-53%, 12 min]).(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(methylsulfonamidomethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(10.00 mg, 16.2 umol, 31.1% yield) was obtained as a light purple solid.¹H NMR (DMSO-d₆, 400 MHz) δ 7.37 (d, J=8.4 Hz, 1H), 7.23-7.15 (m, 2H),7.05 (dd, J=8.4, 2.8 Hz, 1H), 6.10 (dd, J=17.6, 11.2 Hz, 1H), 5.60 (d,J=8.0 Hz, 1H), 5.13-5.10 (m, 1H), 5.04-5.09 (m, 1H), 5.00 (d, J=10.8 Hz,1H), 4.78-4.64 (m, 2H), 3.04 (dt, J=13.6, 6.8 Hz, 1H), 2.87 (s, 3H),2.41 (brs, 1H), 2.24-2.14 (m, 1H), 2.12-2.02 (m, 3H), 1.70-1.30 (m,13H), 1.07-0.96 (m, 4H), 0.82 (d, J=7.2 Hz, 3H), 0.64 (d, J=7.2 Hz, 3H).MS (ESI): mass calcd. for C₃₁H₄₄BNO₉S 617.6, m/z found 635.3 [M+NH₃+H]⁺.HPLC: 100% (220 nm), 100% (254 nm).

24. tert-Butyl2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate25.2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)aceticacid

A solution of 4-(benzyloxy)-2-hydroxybenzaldehyde (42.0 g, 184.0 mmol,1.0 eq.), pyridine (36.4 g, 460.0 mmol, 2.5 eq.) and DMAP (449.6 mg, 3.7mmol, 0.02 eq.) in DCM (1.0 L) was added Tf₂O (77.9 g, 276.0 mmol, 1.5eq.). The mixture was stirred at 25° C. for 2 hours. TLC indicated4-(benzyloxy)-2-hydroxybenzaldehyde was consumed completely. Thereaction mixture was quenched by addition H₂O 500 mL at 25° C., and thenthe organic layer were washed with 0.5 M HCl (aq, 500 mL) and brine 500mL, dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=50/1 to 10:1).5-(benzyloxy)-2-formylphenyl trifluoromethanesulfonate (50.0 g, 138.8mmol, 75.4% yield) was obtained as a colorless oil.

To a solution of 5-(benzyloxy)-2-formylphenyl trifluoromethanesulfonate(80.0 g, 222.0 mmol, 1.0 eq.) in dioxane (200.0 mL) was added KOAc (65.4g, 666.1 mmol, 3.0 eq.), Pd (dppf) Cl₂ (3.2 g, 4.4 mmol, 0.02 eq.) andPin₂B₂ (62.0 g, 244.2 mmol, 3.0 eq.). The mixture was stirred at 80° C.for 12 hours. TLC indicated 5-(benzyloxy)-2-formylphenyl trifluoromethanesulfonate was consumed completely. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=20/1 to 5:1).4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(56.0 g, 165.6 mmol, 74.6% yield) was obtained as a white solid.

To a solution of zinc powder (26.1 g, 399.9 mmol, 1.0 eq.) in THF (2.0L) was added TMSCl (4.0 g, 37.3 mmol, 0.1 eq.), the mixture was stirredat 15° C. for 0.5 hour, and then tert-butyl 2-bromoacetate (78.0 g,399.9 mmol, 1.0 eq.) was added. The mixture was stirred at 15° C. foranother 15 hours. (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (104.1 g,399.7 mmol, 99.9% yield) was obtained as a solution in THF (0.2 M). To asolution of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(2.0 g, 5.9 mmol, 1.0 eq.) in THF (20.0 mL) was addedbromo-(2-tert-butoxy-2-oxo-ethyl) zinc (0.2 M, 206.85 mL, 7.00 eq.). Themixture was stirred at 15° C. for 4 hours. HPLC indicated4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehydewas consumed completely and a new peak was formed, LCMS indicated it wasdesired product. The reaction mixture was quenched by addition H₂O 200mL at 0° C., and then extracted with EtOAc 1200 mL (400 mL×3). Thecombined organic layers were washed with brine 200 mL, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product tert-butyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(2.0 g, 5.6 mmol, 95.5% yield) was used into the next step withoutfurther purification. MS: m/z=399.1 [M−55]⁻

To a solution of tert-butyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500.0 mg, 1.4 mmol, 1.0 eq.) in EtOAC (50.0 mL)was added Pd/C (500.0 mg), the mixture was then stirred at 15° C. for 3hours under H₂ atmosphere (pressure 40 psi). HPLC indicated tert-butyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate was consumed completely and a new peak was formed.The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The crude product tert-butyl2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (350.0mg, 1.3 mmol, 94.0% yield) was used into the next step without furtherpurification. MS: m/z=209.1 [M−55]⁻

To a solution of tert-butyl2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (359.1mg, 1.3 mmol, 1.0 eq.) and(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate(724.4 mg, 1.3 mmol, 1.0 eq.) in DMF (10.0 mL) were added K₂CO₃ (563.9mg, 4.1 mmol, 3.0 eq.) and KI (22.6 mg, 136.0 umol, 0.1 eq.). Themixture was stirred at 50° C. for 15 hours. HPLC indicated tert-butyl2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate wasconsumed completely and a new peak was formed. The reaction mixture wasquenched by addition H₂O 20 mL at 0° C., and then adjusted to pH=7,solid was dissolved, filtered (filter cake) to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex luna C18 250×50mm, 10 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 45%-75%, 20min]). tert-butyl2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(320.0 mg, 506.5 umol, 37.2% yield, 100.0% purity) was obtained as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.14 (s, 1H), 7.16 (s, 1H),7.33 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.10 (dd, J=17.6, 11.2Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.04-5.10 (m, 1H), 5.36 (dd, J=8.0, 4.0Hz, 1H), 5.00 (d, J=11.2 Hz, 1H), 4.64-4.77 (m, 2H), 4.52 (d, J=6.0 Hz,1H), 4.52 (d, J=6.0 Hz, 1H), 3.38-3.46 (m, 1H), 2.87 (dd, J=15.2, 3.2Hz, 1H), 2.41 (br. s., 1H), 2.34 (dd, J=15.2, 8.0 Hz, 1H), 2.13-2.25 (m,1H), 2.01-2.12 (m, 4H), 1.58-1.70 (m, 2H), 1.35-1.39 (m, 7H), 1.32-1.34(m, 4H), 1.29 (d, J=15.2 Hz, 3H), 0.93-1.12 (m, 5H), 0.82 (d, J=6.4 Hz,3H), 0.63 (d, J=6.4 Hz, 3H) MS (ESI): mass calcd. for C₃₅H₄₉BO₉ 624.57,m/z found 563.4 [M−H]⁻. HPLC: 100.0% (220 nm), 87.5% (254 nm).

To a solution of tert-butyl2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(100.0 mg, 160.1 umol, 1.0 eq.) in DCM (15.0 mL) was added CF₃COOH(182.5 mg, 1.6 mmol, 10.0 eq.). The mixture was stirred at 15° C. for 48hours. HPLC indicated tert-butyl2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetatewas consumed completely. The reaction mixture was quenched by additionH₂O 40 mL at 0° C., and then diluted with DCM 20 mL and extracted withDCM 60 mL (30 mL×2). The combined organic layers were washed with H₂O 40mL (20 mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Luna C8 100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v;B-ACN] B %: 35%-65%, 12 min]).2-(1-hydroxy-6-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)aceticacid (51.0 mg, 89.7 umol, 56.0% yield, 100.0% purity) was obtained as awhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.35 (d, J=8.4 Hz, 1H), 7.15(s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.10 (dd, J=11.2, 18.0 Hz, 1H), 5.60(d, J=8.0 Hz, 1H), 5.38 (dd, J=3.6, 8.8 Hz, 1H), 5.11-4.97 (m, 2H),4.79-4.62 (m, 2H), 2.89 (dd, J=3.6, 15.6 Hz, 1H), 2.41 (br. s., 1H),2.27 (dd, J=8.8, 15.6 Hz, 1H), 2.2-2.13 (m, 1H), 2.12-2.02 (m, 3H),1.72-1.57 (m, 2H), 1.52-1.43 (m, 1H), 1.42-1.20 (m, 8H), 1.04 (s, 3H),1.02-0.95 (m, 1H), 0.82 (d, J=6.4 Hz, 3H), 0.63 (d, J=6.4 Hz, 3H) MS(ESI): mass calcd. for C₃₁H₄₁BO₉ 568.46, m/z found 567.3 [M−H]⁻. HPLC:100.0% (220 nm), 87.5% (254 nm).

26.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(2-methoxy-2-oxoethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

A solution of tert-butyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(700.0 mg, 1.9 mmol, 1.0 eq.) in CH₃OH (50.0 mL) was added H₂SO₄ (58.1mg, 592.8 umol, 0.3 eq.). The mixture was stirred at 50° C. for 28hours. HPLC and LCMS indicated tert-butyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetatewas consumed and a main peak was formed, LCMS indicated it was desiredproduct. The reaction mixture was quenched by added saturated NaHCO₃(aq, 30 mL) and removed the excessive MeOH, then the mixture wasextracted with EtOAc 90 mL (30 mL×3). The combined organic layers werewashed with brine 40 mL, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 3:1).methyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(500.0 mg, 1.6 mmol, 80.9% yield) was obtained as a light colorless oil.MS: m/z=311.1 [M−1]⁻

A solution of methyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(500.0 mg, 1.6 mmol, 1.0 eq) in EtOAc (50.0 mL) was added Pc/C (200.0mg). The mixture was stirred at 25° C. for 3 hrs under H₂ (50 psi)atmosphere. HPLC indicated methyl2-(6-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetatewas consumed completely. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The crude productmethyl 2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate(200.0 mg, light yellow oil, 630.6 umol, 39.4% yield, 70% purity) wasused into the next step without further purification. MS: m/z=221.1[M−1]⁻

To a solution of methyl2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (108.0mg, 340.5 umol, 1.0 eq.) and (20R,21R,22S,23R,26S,27R)-22-hydroxy-19,20,26,27-tetramethyl-24-oxo-26-vinyl-21-tricyclotetradecanyl]2-(p-tolyl-sulfonyloxy)acetate (181.4 mg, 340.5 umol, 1.0 eq.) in DMF(8.0 mL) was added K₂CO₃ (141.2 mg, 1.0 mmol, 3.0 eq.) and KI (5.6 mg,34.0 umol, 0.1 eq.). The mixture was stirred at 50° C. for 14 hours.HPLC indicated methyl2-(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate wasconsumed completely. The reaction mixture was quenched by addition H₂O50 mL at 0° C., and then adjusted pH=7 (aq HCl, 2M), light yellow solidwas dissolved out, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (column: Luna C18100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %:40%-70%, 12 min]).(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(2-methoxy-2-oxoethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(95.8 mg, 162.8 umol, 47.8% yield, 99.0% purity) was obtained as a lightyellow solid (combined with ET3173-148-P1). ¹H NMR (DMSO-d₆, 400 MHz) δ7.32 (d, J=8.4 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 7.02 (dd, J=2.0, 8.4 Hz,1H), 6.06 (dd, J=11.2, 18.0 Hz, 1H), 5.58 (d, J=8.4 Hz, 1H), 5.39 (dd,J=3.6, 9.2 Hz, 1H), 5.08-4.95 (m, 2H), 4.75-4.62 (m, 2H), 3.61 (s, 3H),3.38 (d, J=5.6 Hz, 1H), 2.99 (dd, J=4.0, 15.6 Hz, 1H), 2.40-2.29 (m,2H), 2.23-2.12 (m, 1H), 2.11-1.96 (m, 3H), 1.69-1.53 (m, 2H), 1.49-1.41(m, 1H), 1.39-1.29 (m, 6H), 1.29-1.19 (m, 4H), 1.06-0.93 (m, 4H), 0.80(d, J=6.4 Hz, 3H), 0.62 (d, J=6.4 Hz, 3H) MS (ESI): mass calcd. forC₃₅H₄₉BO₉ 582.30, m/z found 581.3 [M−H]⁻. HPLC: 99.0% (220 nm), 88.8%(254 nm).

27.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-((dimethylamino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(10.0 g, 29.5 mmol, 1.0 eq.) in MeOH (50.0 mL) and H₂O (50.0 mL) wereadded NaOH (2.3 g, 59.1 mmol, 2.0 eq.) and nitromethane (5.4 g, 88.7mmol, 3.0 eq.). The mixture was stirred at 15° C. for 12 hours. HPLCindicated4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehydewas consumed completely LCMS indicated it was desired product. Thereaction mixture was quenched by addition H₂O 30 mL at 0° C., and thenadjusted pH=5 (aq. HCl, 2M) at 0° C. The mixture was removed MeOH underreduced pressure, and then extracted with EtOAC 300 mL (100 mL×3). Driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product6-(benzyloxy)-3-(nitromethyl)benzo[c][1,2]oxaborol-1 (3H)-ol (9.3 g,black-brown oil, crude, HPLC indicated major was desired product) wasused into the next step without further purification. MS: m/z=298.1[M−1]⁻.

To a solution of 6-(benzyloxy)-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (10.0 g, 33.4 mmol, 1.0 eq.) in AcOH (100.0 mL) was added Zn(4.3 g, 66.8 mmol, 2.0 eq.). The mixture was stirred at 15° C. for 26hours. HPLC indicated 6-(benzyloxy)-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol was consumed completely and a new peak wasformed. The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The crude product3-(aminomethyl)-6-(benzyloxy)benzo[c][1,2]oxaborol-1(3H)-ol (15.0 g,blackbrown oil, crude) was used into the next step without furtherpurification. MS: m/z=268.2 [M+1]⁺.

A solution of3-(aminomethyl)-6-(benzyloxy)benzo[c][1,2]oxaborol-1(3H)-ol (4.0 g, 7.8mmol, 1.0 eq.) in CH₃CN (80.0 mL) was added NaBH₃CN (734.8 mg, 11.6mmol, 1.5 eq.) and HCHO (780.7 mg, 30% in H₂O, 7.8 mmol, 1.0 eq.). Themixture was stirred at 15° C. for 14 hours. HPLC indicated3-(aminomethyl)-6-(benzyloxy)benzo[c][1,2]oxaborol-1(3H)-ol was consumedcompletely. The reaction mixture was concentrated under reduced pressureto remove CH₃CN. The residue was dissolved in water and trace CH₃CN. Theresidue was purified prep-HPLC (column: Phenomenex luna C18 250×50 mm,10 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 15%-45%, 20min]). 6-(benzyloxy)-3-((dimethylamino)methyl)benzo[c][1,2]oxaborol-1(3H)-ol (900.0 mg, 3.0 mmol, 38.8%yield) was obtained as a black-brown oil. MS: m/z=298.2 [M+1]⁺.

A solution of6-(benzyloxy)-3-((dimethylamino)methyl)benzo[c][1,2]oxaborol-1(3H)-ol(500.0 mg, 1.6 mmol, 1.0 eq) in EtOAc (50.0 mL) was added Pd/C (500.0mg). The mixture was stirred at 15° C. for 18 hours under H₂ atmosphere(50 psi). HPLC indicated6-(benzyloxy)-3-((dimethylamino)methyl)benzo[c][1,2]oxaborol-1 (3H)-olwas consumed completely. The reaction mixture was filtered andconcentrated under reduced pressure to give a residue.3-((dimethylamino)methyl)benzo[c][1,2]oxaborole-1,6(3H)-diol (350.0 mg,crude) was obtained as black-blown oil. MS: m/z=208.2 [M+1]⁺.

A solution of3-((dimethylamino)methyl)benzo[c][1,2]oxaborole-1,6(3H)-diol (110.0 mg,531.3 umol, 1.0 eq) and[(19R,20R,21R,22S,23R,26S,27R,28S)-22-hydroxy-19,20,26,27-tetramethyl-24-oxo-26-vinyl-21-tricyclotetradecanyl]2-(p-tolylsulfonyloxy)acetate (283.0 mg, 531.3 umol, 1.0 eq) in DMF (5.0mL) was added K₂CO₃ (220.3 mg, 1.5 mmol, 3.0 eq) and KI (8.8 mg, 53.1umol, 0.1 eq). The mixture was stirred at 50° C. for 36 hours. HPLCindicated[(19R,20R,21R,22S,23R,26S,27R,28S)-22-hydroxy-19,20,26,27-tetramethyl-24-oxo-26-vinyl-21-tricyclotetradecanyl]2-(p-tolylsulfonyloxy)acetate was consumed completely and one new peakformed. The reaction mixture was quenched by adjusted pH=7 (2M aq. HCl),filtered to give a residue (solvent in DMF). The residue was purified byprep-HPLC (column: Luna C18 100×30 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 28%-58%, 12 min]). Concentrated underreduced pressure to remove CH₃CN and then two drops of aq. HCl (2M) wasadded, freeze-drying to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-((dimethylamino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(11.0 mg, 18.9 umol, 3.5% yield, 99.0% purity) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 7.37 (d, J=8.4 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H),7.08 (d, J=8.8 Hz, 1H), 6.07 (dd, J=11.2, 18.0 Hz, 1H), 5.62-5.44 (m,2H), 5.10-4.93 (m, 2H), 4.77-4.64 (m, 2H), 3.69 (d, J=12.0 Hz, 1H), 3.38(d, J=5.6 Hz, 1H), 3.02-2.94 (m, 1H), 2.91 (s, 3H), 2.85 (s, 3H), 2.66(d, J=6.2 Hz, 2H), 2.38-2.28 (m, 2H), 2.23-2.12 (m, 1H), 2.11-1.97 (m,4H), 1.68-1.53 (m, 2H), 1.40-1.18 (m, 7H), 1.07-0.95 (m, 4H), 0.79 (d,J=7.2 Hz, 3H), 0.60 (d, J=7.2 Hz, 3H) MS (ESI): mass calcd. forC₃₂H₄₇BClNO₇ 567.34, m/z found 568.4 [M+H]⁺. HPLC: 99.0% (220 nm), 88.8%(254 nm).

28.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

NaOH (842.4 mg, 21.1 mmol, 1.5 eq) was added to a solution of4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(5.0 g, 14.0 mmol, 1.0 eq) and nitromethane (2.6 g, 42.1 mmol, 3.0 eq)in H₂O (25 mL) and MeOH (15 mL) at 25° C. and the mixture was stirredfor 12 hours, TLC showed major as desired, water was added to themixture and adjusted pH<4, the aqueous layer was treated with EtOAc, thecrude product was purified by flash chromatography (PE/EA=50/1, 10/1) togive6-(benzyloxy)-7-fluoro-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol(3.4 g, 10.7 mmol, 76.37% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.57 (brs,1H), 7.49-7.31 (m, 6H), 7.30-7.26 (m, 1H), 5.73 (dd, J=2.4, 8.4 Hz, 1H),5.29 (dd, J=3.2, 13.6 Hz, 1H), 5.20 (s, 1H), 4.62 (dd, J=9.6, 13.6 Hz,1H).

HCl (10.2 g, 102.1 mmol, 9.5 eq) was added to a solution of6-(benzyloxy)-7-fluoro-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol(3.4 g, 10.7 mmol, 1.0 eq) and iron powder (3.0 g, 53.6 mmol, 5.0 eq) inMeOH (50 mL) and the mixture was heated to reflux for 4 hours. Themixture was cooled to room temperature. Water was added to the mixture,and filtered. The aqueous layer was treated with EtOAc to give crude3-(aminomethyl)-6-(benzyloxy)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-olhydrochloride (3.1 g, crude).

Boc₂O (3.1 g, 14.3 mmol, 1.5 eq) was added to a solution of3-(aminomethyl)-6-(benzyloxy)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-olhydrochloride (3.1 g, 9.5 mmol, 1.0 eq) and TEA (2.9 g, 28.7 mmol, 3.0eq) in DCM (100 mL) at 25° C. The mixture was stirred at 25° C. for 2hours, Water was added to the mixture and adjusted pH<5, the aqueouslayer was treated with DCM to give crude tert-butyl((6-(benzyloxy)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate(2.5 g, 6.4 mmol, 67.4% yield) as yellow solid.

To a solution of tert-butyl((6-(benzyloxy)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate (1.0 g, 2.5 mmol, 1.0 eq) in EtOAc (100mL) was added Pd/C (500.0 mg, 2.5 mmol, 1.0 eq) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (40 psi) at 15° C. for 2 hours. The reactionmixture was filtered and the filtrate was concentrated to give crudetert-butyl((7-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate(610.0 mg, 2.0 mmol, 79.6% yield) as yellow solid.

To a solution of tert-butyl((7-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate(300.0 mg, 1.0 mmol, 1.0 eq) and Tos-pleuromutilin (537.9 mg, 1.0 mmol,1.0 eq) in DMF (15 mL) was added Na₂CO₃ (321.1 mg, 3.0 mmol, 3.0 eq) andthe mixture was stirred at 40° C. for 10 hours. HPLC showed major asdesired, and water was added to the mixture and filtered to give thecrude product, which was purified by Pre-HPLC (Instrument: ShimadzuLC-8A preparative-HPLC System Mobile phase: A: 0.01M NH₄HCO₃ in H₂O; B:ACN Column: Dasio C18 250×50 mm, 10 μm, Wavelength: 220&254 nm Gradient:a gradient of B % from 30% to 60% in 22 min with hold at initial for 3min ) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(100.0 mg, 152.1 umol, 15.1% yield) as yellow solid. ¹H NMR (DMSO-d₆,400 MHz) δ 9.28 (brs, 1H), 7.22-7.14 (m, 1H), 7.07 (d, J=8.0 Hz, 1H),6.96 (brs, 1H), 6.11 (dd, J=11.2, 18.0 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H),5.11-4.98 (m, 3H), 4.83-4.77 (m, 2H), 4.53 (d, J=5.6 Hz, 1H), 3.41 (m,1H), 3.07 (d, J=7.6 Hz, 2H), 2.41 (s, 1H), 2.03-2.09 (m, 5H), 1.70-1.44(m, 2H), 1.63-1.15 (m, 16H), 1.04 (d, J=5.6 Hz, 3H), 0.81 (d, J=7.2 Hz,3H), 0.62 (d, J=7.2 Hz, 3H). MS (ESI): mass calcd. for C₃₅H₄₉BFNO₉657.6, m/z found 656.3 (M−H)⁻. HPLC: 93.3% (220 nm), 100.0% (254 nm).

29.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetateHydrochloride

HCl/EtOAc (4 M, 3.00 mL) was added to a solution of (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(100.0 mg, 152.1 umol, 1.0 eq) in DCM (20 mL), the mixture was stirredat 25° C. for 2 hours, Petroleum ether was added to the mixture andwhite solid precipitated, the mixture was filtered and the cake wasdried to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(61.0 mg, 102.7 umol, 67.5% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.51 (brs., 1H), 8.14 (brs, 3H), 7.27-7.22 (m, 2H), 6.11 (dd,J=10.8, 18.0 Hz, 1H), 5.60 (d, J=7.6 Hz, 1H), 5.30 (d, J=8.8 Hz, 1H),5.06 (d, J=18.0 Hz, 1H), 5.03 (d, J=10.8 Hz, 1H), 4.86-4.82 (m, 2H),2.84-2.82 (m, 2H), 2.41 (s, 1H), 2.18-2.05 (m, 4H), 1.64-1.20 (m, 9H),1.09-0.94 (m, 4H), 0.83-0.79 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H).MS (ESI): mass calcd. for C₃₀H₄₂BClFNO₇ 593.3, m/z found 558.0 (M+H)⁺.HPLC: 99.0% (220 nm), 96.3% (254 nm).

30.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate31.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetateHydrochloride

To a solution of tert-butyl(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl) methyl carbamate(135 mg, 0.48 mmol) in DMF (3 mL) was added NCS (78 mg, 0.58 mmol). Themixture was stirred at 50° C. overnight. The obtained mixture wasfiltered and purified by prep-HPLC to give tert-butyl(7-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methylcarbamate(70 mg, yield 50%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97(s, 1H), 7.11 (d, J=6.4 Hz, 1H), 7.05 (d, J=6.4 Hz, 1H), 6.94-6.90 (m,1H), 5.03-5.01 (m, 1H), 3.08-3.03 (m, 1H), 1.35 (s, 9H). MS (ESI): masscalcd. for C₁₃H₁₇BClNO₃ 313.09, m/z found 336.0 [M+Na]⁺.

To a solution of tert-butyl(7-chloro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methylcarbamate(100 mg, 0.32 mmol), Tos-Pleu (204 mg, 0.38 mmol) and K₂CO₃ (88 mg, 0.64mmol) in acetonitrile (5 mL) was added KI (10 mg, 0.064 mmol). Themixture was stirred at 80° C. overnight. After cooled to roomtemperature, the mixture was filtered and the solvent was removed underreduced pressure. The residue was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(100 mg, yield 47%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13(b, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.20-7.13 (m, 1H), 6.99 (t, J=5.6 Hz,1H), 6.11-6.07 (m, 1H), 5.59 (d, J=7.6 Hz, 1H), 5.11-4.83 (m, 5H),3.41-3.08 (m, 3H), 2.42 (s, 1H), 2.23-2.02 (m, 4H), 1.67-1.04 (m, 23H),0.82 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H). HPLC purity: 100% (220nm); MS (ESI): mass calcd. for C₃₅H₄₉BClNO₉ 673.32, m/z found 696.2[M+Na]⁺.

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(((tert-butoxycarbonyl)amino)methyl)-7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(60 mg, 0.09 mmol) in THF (3 mL) was added HCl/1,4-dioxane (4 M, 0.5mL). The mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure and the residue was purified byprep-HPLC under basic condition to give target as free amine. To asolution of free amine in MeCN (2 mL) was added HCl (2 mL, 0.5 M). Themixture was freeze-dried to give product as HCl salt (34 mg, yield 67%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.13 (s,3H), 7.40 (d, J=8.4 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 6.15-6.08 (m, 1H),5.60 (d, J=7.2 Hz, 1H), 5.29 (d, J=8.0 Hz, 1H), 5.14-4.57 (m, 5H),3.47-3.38 (m, 3H), 2.87 (b, 1H), 2.42 (s, 1H), 2.23-2.02 (m, 4H),1.67-1.05 (m, 14H), 0.82 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.8 Hz, 3H). HPLCpurity: 100% (220 nm); MS (ESI): mass calcd. for C₃₀H₄₁BClNO₇ 573.27,m/z found 574.2 [M+H]⁺.

32.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetate

Sodium hydride (60% in oil, 190 mg, 4.76 mmol) was added to a solutionof benzo[c][1,2]oxaborole-1,5(3H)-diol (269 mg, 1.79 mmol) in 5 mL ofDMF. After the suspension was stirred at 50° C. for two hours, asolution of Tos-pleuromutilin (634 mg, 1.19 mmol) in 5 mL DMF was added.The mixture was stirred at room temperature overnight. The crude waspurified by prep HPLC (column: SunFire C18 OBD 100×30 mm, 5 μm) elutedwith gradient water/acetonitrile (0.1% TFA) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetate as whiteflakes. ¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (s, 1H), 7.54 (d, J=7.2 Hz,1H), 6.82 (m, 2H), 6.03 (dd, J=17.6, 11.2 Hz, 1H), 5.54 (d, J=8.4 Hz,1H), 5.00 (m, 2H), 4.81 (s, 2H), 4.70 (m, 2H), 4.51 (d, J=6 Hz, 1H),3.36 (m, 1H), 2.35 (s, 1H), 2.11-1.97 (m, 4H), 1.68-1.17 (m, 10H), 0.92(m, 4H), 0.74 (d, J=7.2 Hz, 3H), 0.56 (d, J=7.2 Hz, 3H). HPLC: 100% (220nm), 100% (254 nm).

33.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetate

Sodium hydride (60% in oil, 190 mg, 4.76 mmol) was added to a solutionof 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (301 mg, 1.79 mmol) in 5mL of DMF. After the suspension was stirred at 50° C. for two hours, asolution of Tos-pleuromutilin (634 mg, 1.19 mmol) in 5 mL DMF was added.The mixture was stirred at room temperature overnight. The crude waspurified by prep HPLC (column: SunFire C18 OBD 100×30 mm, 5 μm) elutedwith gradient water/acetonitrile (0.1% TFA) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetateas white flakes. ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 6.73 (s, 1H),6.60 (d, J=10 Hz, 1H), 6.03 (dd, J=18.0, 11.2 Hz, 1H), 5.54 (d, J=8.4Hz, 1H), 4.97 (m, 2H), 4.84 (s, 2H), 4.75 (m, 2H), 4.51 (d, J=6 Hz, 1H),3.36 (m, 1H), 2.35 (s, 1H), 2.13-1.96 (m, 4H), 1.61-1.17 (m, 10H),0.98-0.91 (m, 4H), 0.75 (d, J=7.2 Hz, 3H), 0.57 (d, J=6.8 Hz, 3H). MS(ESI): mass calcd. For C₂₉H₃₈BO₇F 528.42, m/z found 586.0 [M+59−H]⁻.HPLC: 100% (220 nm), 100% (254 nm).

34.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetate

Sodium hydride (60% in oil, 190 mg, 4.76 mmol) was added to a solutionof 6-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (300 mg, 1.79 mmol) in 5mL of DMF. After the suspension was stirred at 50° C. for two hours, asolution of Tos-pleuromutilin (634 mg, 1.19 mmol) in 5 mL DMF was added.The mixture was stirred at room temperature overnight. The crude waspurified by prep HPLC (column: SunFire C18 OBD 100×30 mm, 5 μm) elutedwith gradient water/acetonitrile (0.1% TFA) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)acetateas white flakes. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H), 7.39 (d,J=10.4 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.03 (dd, J=18.0, 11.2 Hz, 1H),5.53 (d, J=8.0 Hz, 1H), 4.96 (m, 2H), 4.81 (d, 2H), 4.78 (s, 2H), 4.50(d, J=6 Hz, 1H), 3.36 (m, 1H), 2.35 (s, 1H), 2.08-1.96 (m, 4H),1.60-1.19 (m, 10H), 0.98-0.93 (m, 4H), 0.74 (d, J=6.8 Hz, 3H), 0.56 (d,J=7.2 Hz, 3H). MS (ESI): mass calcd. For C₂₉H₃₈BO₇F 528.42, m/z found527.2 [M−H]⁻. HPLC: 100% (220 nm), 100% (254 nm).

35.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate 36.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate37.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

A mixture of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-hydroxyacetate (30.0 g, 79.8 mmol, 1.0 eq) and NaOH (50% w/w, 12.0 g,303.0 mmol, 3.8 eq) in ethanol (100.0 mL)/water (60.0 mL) was stirred at50° C. for 3 hours. The mixture was concentrated. The crystallineproduct was isolated by filtration, washed with water (100 mL) andheptanes (100 mL), and then dried under vacuum to provide (25.0 g, 98.0%yield) of (3aR,4R,5R,7S,8S,9R,9aS,12R)-5,8-dihydroxy-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-3(3aH)-one.¹H NMR (CDCl₃, 400 MHz) δ 6.15 (dd, J=11.2, 17.6 Hz, 1H), 5.44-5.23 (m,2H), 4.42-4.29 (m, 1H), 3.41 (t, J=6.4 Hz, 1H), 2.33-2.11 (m, 3H), 2.05(s, 1H), 1.98-1.86 (m, 1H), 1.80-1.38 (m, 7H), 1.36 (s, 2H), 1.31 (d,J=5.6 Hz, 1H), 1.15 (s, 3H), 0.96 (d, J=7.2 Hz, 3H), 0.92 (d, J=7.2 Hz,3H).

(3aR,4R,5R,7S,8S,9R,9aS,12R)-5,8-dihydroxy-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-3(3aH)-one(21.0 g, 65.6 mmol, 1.0 eq) and sodium methylate (5.0 g, 92.6 mmol) inethyl formate (150.0 mL) and toluene (100.0 mL) were stirred at 25° C.for 12 hours. Ice was added and the mixture was adjusted pH<4 with 2 NHCl, the aqueous layer was treated with EtOAc (100 mL), the crudeproduct was purified by flash chromatography to give(3aR,4R,5R,7S,8S,9R,9aS,12R,E)-5-hydroxy-2-(hydroxymethylene)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (6.0 g, 24.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, J=0.8Hz, 1H), 6.99 (s, 1H), 6.10 (dd, J=11.4, 17.6 Hz, 1H), 5.45 (dd, J=1.0,17.6 Hz, 1H), 5.29 (s, 1H), 5.04 (d, J=6.8 Hz, 1H), 4.33 (d, J=7.8 Hz,1H), 2.56-2.43 (m, 2H), 2.26 (t, J=7.2 Hz, 1H), 2.08-1.95 (m, 1H),1.87-1.58 (m, 3H), 1.49-1.33 (m, 5H), 1.02 (s, 3H), 1.00 (d, J=7.2 Hz,3H), 0.81 (d, J=7.2 Hz, 3H).

Tosyl azide (4.7 g, 24.0 mmol) was added to a cooled solution of(3aR,4R,5R,7S,8S,9R,9aS,12R,E)-5-hydroxy-2-(hydroxymethylene)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (6.0 g, 16.0 mmol) and TEA (7.2 g, 71.0 mmol) in anhydrous DCM(50.0 mL) at −15° C., the mixture was stirred at room temperature for 3hours. Major as desired, and the crude product was purified by flashchromatography to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-2-diazo-5-hydroxy-3a,4,7,9,12-pentamethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (3.5 g, 55.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (s, 1H),6.09 (dd, J=11.2, 17.8 Hz, 1H), 5.46 (dd, J=1.2, 17.8 Hz, 1H), 5.34-5.28(m, 1H), 5.02 (d, J=6.6 Hz, 1H), 4.30 (t, J=6.4 Hz, 1H), 3.08 (d, J=13.2Hz, 1H), 2.46 (d, J=2.2 Hz, 1H), 2.28 (t, J=6.8 Hz, 1H), 2.20 (d, J=12.8Hz, 1H), 1.98 (dd, J=7.6, 16.1 Hz, 1H), 1.84-1.67 (m, 3H), 1.63-1.37 (m,6H), 1.32 (d, J=5.6 Hz, 1H), 1.03 (s, 3H), 0.99 (d, J=7.2 Hz, 3H), 0.84(d, J=7.2 Hz, 3H).

Dichloroacetic acid (2.0 mL) was added to a cooled solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-2-diazo-5-hydroxy-3a,4,7,9,12-pentamethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (1.0 g, 2.5 mmol) in anhydrous DCM (30.0 mL) at −15° C., themixture was stirred at 25° C. for 12 hours. The solvent was evaporated,the crude product was purified by prep-HPLC to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-8-(formyloxy)-5-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (0.6 g, 48.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.16(s, 1H), 6.09 (dd, J=11.2, 17.8 Hz, 1H), 6.00 (s, 1H), 5.45 (d, J=17.8Hz, 1H), 5.32 (d, J=11.2 Hz, 1H), 5.09 (t, J=9.0 Hz, 1H), 4.91 (d, J=6.8Hz, 1H), 4.30 (d, J=7.2 Hz, 1H), 2.39 (d, J=2.8 Hz, 1H), 2.27 (t, J=6.8Hz, 1H), 2.12 (dd, J=8.8, 13.4 Hz, 1H), 2.05-1.86 (m, 3H), 1.78 (d,J=16.0 Hz, 1H), 1.56-1.37 (m, 4H), 1.04 (s, 3H), 1.00 (d, J=6.4 Hz, 3H),0.85 (d, J=7.2 Hz, 3H).

Chloroacetyl chloride (0.9 g, 7.6 mmol) was added to a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-8-(formyloxy)-5-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (1.2 g, 2.5 mmol) and pyridine (1.2 g, 15.0 mmol) inDCM (30.0 mL) at 0° C. The mixture was stirred at 25° C. for 2 hours,water (30 mL) was added, and the aqueous layer was treated with DCM (30mL×3). The crude product was purified by prep-HPLC to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-5-(2-chloroacetoxy)-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (0.8 g, 54.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.15(s, 1H), 6.31 (dd, J=11.2, 17.4 Hz, 1H), 6.00 (s, 1H), 5.72 (d, J=8.0Hz, 1H), 5.36-5.19 (m, 2H), 5.10 (t, J=8.8 Hz, 1H), 4.96 (d, J=6.5 Hz,1H), 3.99 (d, J=1.8 Hz, 2H), 2.52-2.45 (m, 2H), 2.26-2.09 (m, 4H),2.01-1.89 (m, 1H), 1.63-1.38 (m, 8H), 1.12-1.04 (m, 3H), 0.87 (d, J=6.8Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-5-(2-chloroacetoxy)-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (0.3 g, 0.5 mmol),benzo[c][1,2]oxaborole-1,6(3H)-diol (81.0 mg, 0.5 mmol) and potassiumcarbonate (225.0 mg, 1.6 mmol) with cata. amount sodium iodide in DMF(15.0 mL) were stirred at 50° C. for 12 hours. Water (15 mL) was added,the mixture was filtered and dried to give crude (2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-8-(formyloxy)-5-(2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetoxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (0.3 g, crude) and used directly.

Sodium hydroxide (30.0 mg, 0.8 mmol) was added to (2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-8-(formyloxy)-5-(2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetoxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (0.3 g, 0.4 mmol) in EtOH (10.0 mL) and water (10.0mL). The mixture was stirred at 25° C. for 15 mins, the mixture wasadjusted pH<4 with 2N HCl. Solvent was evaporated, the crude product waspurified by prep-HPLC to give (2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (35.0mg, 17.5% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.09 (br. s., 1H), 7.30(d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.04 (dd, J=2.4, 8.4 Hz, 1H), 6.09 (dd,J=11.0, 17.6 Hz, 1H), 5.59 (d, J=7.6 Hz, 1H), 5.12-4.97 (m, 2H), 4.91(s, 2H), 4.78-4.65 (m, 3H), 3.75 (t, J=8.4 Hz, 1H), 3.32 (d, J=5.8 Hz,1H), 2.35 (br. s., 1H), 2.12-1.96 (m, 2H), 1.87-1.71 (m, 2H), 1.46-1.27(m, 7H), 1.22 (br. s., 1H), 1.05 (s, 3H), 0.83 (d, J=6.8 Hz, 3H), 0.64(d, J=5.8 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₉BO₈ 526.27, m/z found525.2 [M−H]⁻. HPLC: 99.7% (220 nm), 73.1% (254 nm).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate was synthesized similarly by using7-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol. ¹H NMR (DMSO-d₆, 400 MHz) δ7.18 (br. s., 1H), 7.09 (br. s., 1H), 6.09 (dd, J=11.2, 17.8 Hz, 1H),5.58 (d, J=8.8 Hz, 1H), 5.10-4.97 (m, 2H), 4.91 (br. s., 1H), 4.78 (br.s., 2H), 3.74 (t, J=8.4 Hz, 1H), 3.42 (q, J=7.2 Hz, 1H), 3.30 (d, J=6.2Hz, 1H), 2.33 (br. s., 1H), 2.12-1.96 (m, 3H), 1.87-1.69 (m, 2H),1.48-1.17 (m, 7H), 1.10-1.00 (m, 4H), 0.82 (d, J=7.2 Hz, 2H), 0.63 (br.s., 2H). MS (ESI): mass calcd. for C₂₉H₃₈BFO₈ 544.26, m/z found 543.3[M−H]⁻. HPLC: 99.8% (220 nm), 81.1% (254 nm).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatewas synthesized similarly by using5-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol. ¹H NMR (DMSO-d₆, 400 MHz) δ9.11 (s, 1H), 7.38-7.27 (m, 2H), 6.07 (dd, J=11.4, 17.6 Hz, 1H),5.64-5.51 (m, 2H), 5.12-4.96 (m, 2H), 4.90 (br. s., 2H), 4.87-4.74 (m,2H), 4.65 (d, J=5.8 Hz, 1H), 3.75 (d, J=7.2 Hz, 1H), 2.35 (br. s., 1H),2.13-1.93 (m, 2H), 1.87-1.67 (m, 2H), 1.46-1.16 (m, 8H), 1.04 (br. s.,4H), 0.82 (d, J=6.4 Hz, 3H), 0.63 (br. s., 3H). MS (ESI): mass calcd.for C₂₉H₃₉O₈ 544.3, m/z found 543.3 [M−H]⁻. HPLC: 98.9% (220 nm), 100.0%(254 nm).

38.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate 39.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate40.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

Hydrogen fluoride pyridine complex (35.0 mL) was added to a cooledsolution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-2-diazo-5-hydroxy-3a,4,7,9,12-pentamethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (11.0 g, 28.3 mmol) in anhydrous THF (100.0 ml) at −15° C. Themixture was stirred at 25° C. for 12 hours. Water (100 mL) was added,the aqueous layer was treated with EtOAc (150 mL), the crude product waspurified by flash chromatography to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-5-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (4.0 g, 38.7% yield). ¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, J=1.2Hz, 1H), 6.10 (ddd, J=1.2, 11.2, 17.8 Hz, 1H), 5.45 (dd, J=1.2, 17.8 Hz,1H), 5.35-5.27 (m, 1H), 4.92 (d, J=6.6 Hz, 1H), 4.79-4.70 (m, 1H),4.64-4.57 (m, 1H), 4.29 (d, J=3.2 Hz, 1H), 2.39 (d, J=3.2 Hz, 1H),2.33-2.18 (m, 1H), 2.14-1.85 (m, 4H), 1.77 (d, J=16.2 Hz, 1H), 1.63-1.23(m, 8H), 1.04 (s, 2H), 1.01-0.97 (m, 2H), 0.85 (d, J=7.2 Hz, 3H).

2-(tosyloxy)acetic acid (2.6 g, 11.3 mmol), PFPOH (2.5 g, 13.5 mmol),DCC (2.8 g, 13.5 mmol) and cata amount DMAP in anhydrous THF (50.0 mL)were stirred at 25° C. for 15 hours. The mixture was filtered, the crudeproduct was purified by flash chromatography to give perfluorophenyl2-(tosyloxy) acetate (2.1 g, 47.0% yield). ¹H NMR (CDCl₃, 400 MHz) δ7.87 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.97 (s, 2H), 2.48 (s,3H).(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-5-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-8-ylformate (4.0 g, 10.9 mmol), perfluorophenyl 2-(tosyloxy)acetate (10.8 g,27.0 mmol) and DMAP (1.3 g, 10.9 mmol) in anhydrous THF (100.0 mL) werestirred at 25° C. for 12 hours. The solvent was evaporated, the crudeproduct was purified by Pre-HPLC to give (2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (2.7 g, yield 43%). 1H NMR (CDCl₃, 400 MHz) δ 8.16(s, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.23 (dd,J=17.6, 11.2 Hz, 1H), 5.68 (d, J=8.4 Hz, 1H), 5.14-5.37 (m, 1H), 4.93(d, J=6.4 Hz, 1H), 4.75 (t, J=8.0 Hz, 1H), 4.62 (t, J=8.0 Hz, 1H), 4.50(s, 2H), 2.38-2.51 (m, 5H), 1.85-2.17 (m, 5H), 1.66 (s, 2H), 1.30-1.57(m, 7H), 1.05 (s, 3H), 0.85 (d, J=6.8 Hz, 4H).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (1.5 g, 2.6 mmol),benzo[c][1,2]oxaborole-1,6(3H)-diol (3890 mg, 2.6 mmol) and potassiumcarbonate (1.1 g, 7.7 mmol) with cata. Amount sodium iodide in DMF (30.0mL) was stirred at 50° C. for 1 hour. Water (50 mL) was added, themixture was filtered and dried to give crude(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (1.6 g,crude) and used directly. Potassium carbonate (794.0 mg, 5.8 mmol) wasadded to (2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy) acetate (1.6 g,crude, 2.9 mmol) in MeOH (50.0 mL) and THF (50.0 mL). The mixture wasstirred at 50° C. for 2 hours, the mixture was adjusted pH<4 with 2NHCl. Solvent was evaporated, the crude product was purified by prep-HPLCto give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate (230.0mg, 15.0% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.30 (d, J=8.4 Hz, 1H),7.20 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.14-6.03 (m, 1H), 5.57 (d, J=8.4Hz, 1H), 5.11-4.97 (m, 3H), 4.91 (s, 2H), 4.85 (t, J=9.0 Hz, 1H),4.79-4.65 (m, 2H), 3.34 (br. s., 1H), 2.61 (br. s., 1H), 2.26-1.97 (m,4H), 1.81 (d, J=15.2 Hz, 1H), 1.67-1.17 (m, 7H), 1.05 (s, 3H), 0.84 (d,J=6.4 Hz, 3H), 0.64 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. forC₂₉H₃₈BFO₇ 528.27, m/z found 526.9 [M−H]⁻. HPLC: 93.5% (220 nm), 71.9%(254 nm).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatewas synthesized similarly as above by using7-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol. ¹H NMR (DMSO-d₆, 400 MHz) δ7.25-7.18 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.09 (dd, J=11.4, 18.1 Hz,1H), 5.57 (d, J=7.8 Hz, 1H), 5.10-4.98 (m, 2H), 4.92 (s, 2H), 4.88 (br.s., 1H), 4.83 (d, J=4.8 Hz, 2H), 3.34 (br. s., 1H), 2.61 (br. s., 1H),2.27-1.93 (m, 3H), 1.80 (d, J=13.3 Hz, 1H), 1.70-1.18 (m, 10H), 1.05(br. s., 3H), 0.84 (d, J=6.8 Hz, 3H), 0.63 (d, J=6.0 Hz, 3H). MS (ESI):mass calcd. for C₂₉H₃₇BF₂O₇546.26, m/z found 563.3 [M+H₂O−H]⁻. HPLC:97.8% (220 nm), 100.0% (254 nm).

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetatewas synthesized similarly as above by using5-fluorobenzo[c][1,2]oxaborole-1,6(3H)-diol. ¹H NMR (DMSO-d₆, 400 MHz) δ7.36-7.28 (m, 2H), 6.06 (dd, J=12.0, 17.4 Hz, 1H), 5.56 (d, J=8.2 Hz,1H), 5.10-4.96 (m, 3H), 4.90 (s, 2H), 4.85 (br. s., 1H), 4.82 (d, J=5.6Hz, 2H), 3.34 (s, 1H), 2.61 (br. s., 1H), 2.22-1.92 (m, 3H), 1.80 (d,J=14.6 Hz, 1H), 1.67-1.17 (m, 9H), 1.04 (s, 3H), 0.84 (d, J=6.4 Hz, 2H),0.63 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₇BF₂O₇ 546.26,m/z found 545.3 [M−H]⁻. HPLC: 96.4% (220 nm), 91.5% (254 nm).

41.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate42.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate

To a solution of tert-butyl(1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate (28mg, 0.1 mmol) and K₂CO₃ (27 mg, 0.2 mmol) in MeCN (5 mL) was added(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-iodoacetate (50 mg, 0.1 mmol). The reaction mixture was heated toreflux overnight. After removed the solvent, the residue was purified byprep-HPLC to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(13 mg, yield 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08(s, 1H), 7.37 (t, J=5.2 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.17-6.03(m, 1H), 5.58 (d, J=7.6 Hz, 2H), 5.15-4.99 (m, 2H), 4.93 (s, 2H),4.74-4.60 (m, 3H), 4.05 (d, J=5.6 Hz, 2H), 3.76 (s, 1H), 2.36-1.75 (m,6H), 1.43-0.63 (m, 28H). HPLC purity: 100% (214 nm); MS (ESI): masscalcd. for C₃₅H₅₀BNO₁₀ 655.35, m/z found 556.2 [M−99]⁺.

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(8 mg, 0.012 mmol) in MeOH (3 mL) was added HCl/1,4-dioxane (4 N, 0.5mL). The reaction mixture was stirred at r.t for 3 h. The solvent wasremoved and the residue was purified by prep-HPLC to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)acetate(1.2 mg, yield 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03(s, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.13-6.04 (m,1H), 5.60-5.55 (m, 2H), 5.10-4.99 (m, 2H), 4.95 (s, 2H), 4.75-4.64 (m,3H), 3.77-3.72 (m, 1H), 3.64 (s, 2H), 2.41-1.95 (m, 5H), 1.39-0.64 (m,22H). HPLC purity: 100% (220 nm); MS (ESI): mass calcd. for C₃₀H₄₂BNO₈555.30, m/z found 556.2 [M+H]⁺.

43.(3aR,4R,5R,7S,9R,9aS,12R)-4,7,9,12-tetramethyl-3,8-dioxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate

(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-hydroxyacetate (40.0 g, 106.0 mmol) was dissolved in methanol (150 mL)and trimethyl orthoformate (50.0 g, 475.0 mmol) at 20° C. Concentratedsulphuric acid (19.8 g, 206.0 mmol) was added over 10 min at <30° C. Themixture was heated to 30° C. and stirred for 16 hrs. A solution of NaOH(32.0 g, 0.8 mol) in water (35 mL) was added to the methanol mixture,and the contents were heated to 60-70° C. for 2 h. The mixture wascooled to 40° C., and methanol was removed by vacuum. The reactionmixture was extracted with ethyl acetate for three times, the combinedorganic phases were washed by brine, dried over Na₂SO₄. The solvent wasremoved to give(3R,3aR,4R,5R,7S,9R,9aR,12R)-5-hydroxy-3-methoxy-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-8(9H)-oneand (30.0 g, 84.5% yield) used for the next step directly. ¹H NMR(DMSO-d₆, 400 MHz) δ 6.05 (dd, J=10.8 Hz, 1H), 5.29 (m, 2H), 4.66 (d,J=8.8 Hz, 1H), 3.48 (m, 1H), 3.22 (s, 3H), 2.92 (m, 1H), 2.45 (m, 1H),2.18 (m, 1H), 1.99 (m, 3H), 1.85 (d, 1H), 1.71 (d, 1H), 1.58 (m, 2H),1.46 (m, 1H), 1.32 (m, 1H), 1.18 (m, 7H), 1.09 (d, 3H), 0.95 (d, 3H).

Trichloromethylchloroformate (215.0 mL, 1.5 mmol) followed Et₃N (495.0mL, 3.6 mmol) was added to an-ice-cooled solution of(3R,3aR,4R,5R,7S,9R,9aR,12R)-5-hydroxy-3-methoxy-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-8(9H)-one(1.0 g, 3.0 mmol) in THF (10 mL). The mixture was stirred at r.t for 2hrs and then treated with further quantities ofTrichloromethylchloroformate (215.0 mL, 1.5 mmol) and Et₃N (495.0 mL,3.6 mmol). After a further 2 hrs, the mixture was diluted with EtOAc andwashed by brine. The organic phase was dried by Na₂SO₄, concentrated togive(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate without further purification. (1.2 g, 100.0%).

To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (200.0 mg, 1.4mmol) in DCM (15 mL) were added Et₃N (137.0 mg, 1.4 mmol) and(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate (1.2 g, 3.0 mmol). The reaction mixture was stirred atr.t overnight, After TLC showed the staring materials were consumedcompletely, and the mixture was extracted with EtOAc, washed with brine,dried over anhydrous Na₂SO₄, and concentrated in vacuo give the crudecompound which was used for the next step directly. (crude 1.3 g)

The mixture of(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate (crude 1.3 g) was added the solution of ZnCl₂ inconc.HCl. The mixture was stirred at r.t for 0.5 hr. Then the mixturewas added water and extracted with EtOAc. The crude product was purifiedby pre-HPLC to give (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate. (61.0 mg).¹H NMR (DMSO-d₆, 400 MHz) δ 9.38 (s, 1H), 7.89 (s, 1H), 7.43 (d, J=7.6Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 6.26 (m, 1H), 5.58 (s, 1H), 5.13 (m,2H), 4.89 (s, 2H), 2.38 (m, 1H), 2.05 (m, 4H), 1.06-1.50 (m, 13H), 1.07(m, 4H), 0.82 (d, 3H), 0.69 (d, 3H).

44.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate

To a solution of 6-amino-5-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol (200mg, 1.2 mmol) in THF (15 mL) were added pyridine (1.2 g, 18 mmol) and(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate (1.4 g, 3.5 mmol). The reaction mixture was stirred atroom temperature overnight. After TLC showed the staring materials wereconsumed completely, and the mixture was extracted with EtOAc, washedwith brine, dried over anhydrous Na₂SO₄, and concentrated in vacuum givethe crude product which was purified by prep-HPLC (column: Luna C18100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %:40%-70%, 15 min]) to give(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate (400mg, 64.2% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.25 (s,2H), 7.99 (s, 1H), 7.32 (d, J=10.4 Hz, 1H), 6.74 (dd, J=10.8, 17.6 Hz,1H), 5.64 (d, J=9.6 Hz, 1H), 5.29 (d, J=10.8 Hz, 1H), 4.98 (m, 3H), 3.40(s, 1H), 3.12 (s, 3H), 2.88 (m, 1H), 2.34 (m, 1H), 2.04 (s, 3H), 1.90(m, 1H), 1.72 (m, 1H), 1.67 (d, 2H), 1.43 (m, 2H), 1.25-1.07 (m, 9H),0.87-0.75 (m, 5H). MS (ESI): mass calcd. for C₂₉H₃₉BNO₆ 527.2, m/z found526.2 [M−H]⁻. HPLC: 99.6% (220 nm), 100% (254 nm).

(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate(300.0 mg, 0.6 mmol) was added to the solution of ZnCl₂ in conc.HCl (10mL, 50% wt). The mixture was stirred at room temperature for 0.5 h. Thenthe mixture was diluted with water (50 mL) and extracted with EtOAc (50mL) three times. The crude product was purified by prep-HPLC (column:Luna C18 100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B%: 35%-60%, 20 min]) to give the(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamate(82.0 mg, 28.2% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.22 (s, 1H), 9.06(s, 1H), 7.90 (s, 1H), 7.26 (d, J=10.8 Hz, 1H), 6.25 (dd, J=10.8, 17.6Hz, 1H), 5.52 (d, J=8.0 Hz, 1H), 5.11 (d, J=18.0 Hz, 1H), 5.04 (d,J=10.8 Hz, 1H), 4.91 (s, 2H), 4.46 (d, J=6.0 Hz, 1H), 3.40 (m, 1H), 2.37(s, 1H), 2.13-2.06 (m, 4H), 1.70-1.25 (m, 10H), 1.06 (m, 4H), 0.80 (d,J=7.2 Hz, 3H), 0.71 (d, J=7.2 Hz, 3H). MS (ESI): mass calcd. forC₂₈H₃₇BFNO₆ 513.2, m/z found 512.2 [M−H]⁻. HPLC: 96.4% (220 nm), 100%(254 nm).

45.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To a solution of 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (299.4 mg, 2.0mmol, 1.0 eq.) and Iodo-pleoromutilin (981.7 mg, 2.0 mmol, 1.0 eq.) inDMF (40.0 mL) was added K₂CO₃ (833.4 mg, 6.0 mmol, 3.0 eq.). The mixturewas stirred at 40° C. for 16 hours. HPLC indicated6-aminobenzo[c][1,2]oxaborol-1(3H)-ol was consumed completely two newpeaks formed. The reaction mixture was quenched by addition H₂O 100 mL,and then adjusted pH˜6, solid was dissolved out, filtered to give aresidue. The residue was purified by prep-HPLC (column: Phenomenex luna(2) C18 250×50 mm, 10 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B%: 20 min]), removed CH₃CN, and then a drop of 2 N HCl was added,freeze-dried to give the product.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl) amino)acetatehydrochloride (138.0 mg, 252.8 umol, 12.6% yield) was obtained as ayellow solid (detected by ¹H NMR). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.09 (d,J=8.4 Hz, 1H), 6.83 (br. s., 1H), 6.72 (d, J=8.4 Hz, 1H), 6.12-5.96 (m,1H), 5.53 (d, J=8.0 Hz, 1H), 5.07-4.90 (m, 2H), 4.87-4.77 (m, 1H), 3.78(d, J=5.2 Hz, 2H), 3.37 (d, J=5.2 Hz, 1H), 2.33 (br. s., 1H), 2.22-2.12(m, 1H), 2.10-1.91 (m, 3H), 1.70-1.52 (m, 3H), 1.43 (br. s., 2H),1.37-1.15 (m, 8H), 1.06-0.89 (m, 5H), 0.79 (d, J=6.4 Hz, 3H), 0.61 (d,J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₄₁BClNO₆ 545.27, m/z found508.3 [M−H]⁻. HPLC: 100.0% (220 nm), 100.0% (254 nm).

46.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To a solution of(3aR,4S,5S,7S,8S,9R,9aS,12R)-8-hydroxy-5-(3-iodo-2-oxopropyl)-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-3(3aH)-one(50.0 mg, 0.1 mmol) in NMP (5 mL) were added K₂CO₃ (73.6 mg, 0.2 mmol)and 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (16.7 mg, 0.1 mmol).The reaction mixture was irradiated under microwave at 100° C. for 2hrs, extracted with EtOAc (10 mL×3). The combined organic phases weredried over anhydrous Na₂SO₄, and concentrated in vacuum give the crudecompound which was purified by prep-HPLC to obtained(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((5-fluoro-1-hydroxy-1,3-di-hydrobenzo[c][1,2]oxaborol-6-yl)amino)acetate(25.0 mg, 47.4%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.88 (s,1H), 7.11-7.09 (d, J=8.0 Hz, 1H), 6.88-6.86 (d, J=8.0 Hz, 1H), 6.09-6.04(m, 1H), 5.75 (s, 1H), 5.54-5.42 (d, J=8.0 Hz, 1H), 5.05-5.01 (m, 1H),4.95-4.93 (m, 1H), 4.83 (s, 2H), 3.86-3.83 (m, 2H), 2.37-2.17 (m, 1H),2.14-2.08 (m, 2H), 2.06-2.01 (m, 3H), 1.66-1.62 (m, 3H), 1.59-1.32 (m,5H), 1.24-1.21 (m, 4H), 1.00 (s, 3H), 0.81-0.79 (d, J=8.0 Hz, 3H),0.62-0.61 (d, J=4.0 Hz, 3H).

47.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

A mixture of 4-bromo-3-methylbenzonitrile (15.0 g, 76.9 mmol, 1 eq), NBS(16.3 g, 92.3 mmol, 1.2 eq) and AIBN (0.95 g, 3.8 mmol, 5%) in CCl₄ (220ml) was stirred at 78° C. for overnight. The mixture was filtered, thenthe clear solution was washed by brine, dried with Na₂SO₄ andconcentrated in vacuum to give 4-bromo-3-(bromomethyl)benzonitrile (16.0g) as a brown solid.

A mixture of 4-bromo-3-(bromomethyl)benzonitrile (crude product, 15.0 g,54.6 mmol, 1 eq), and KOAc (15.9 g, 163.5 mmol, 3.0 eq) in DMF (135 mL)was stirred at 80° C. for 2 h. The mixture was filtered and then theclear solution was washed by brine, dried with Na₂SO₄, concentrated invacuum to give 2-bromo-5-cyanobenzyl acetate (15.6 g) as a brown solid.

A mixture of 2-bromo-5-cyanobenzyl acetate (crude product, 13.5 g, 54.6mmol, 1.0 eq), NaOH (2.55 g, 63.9 mmol, 1.2 eq) in methanol (150 ml) andwater (50 mL) was stirred at room temperature for 2 h. The water (150ml) was added to mixture. Then the mixture was extracted with EA (3×60mL) and the organic phase was washed by brine, dried with Na₂SO₄,concentrated in vacuum to give 4-bromo-3-(hydroxymethyl)benzonitrile(14.0 g) as brown solid.

A solution of 4-bromo-3-(hydroxymethyl)benzonitrile (crude product, 13.5g, 63.0 mmol, 1.0 eq), DIEA (24.6 g, 190.8 mmol, 3.0 eq) and(chloromethoxy)ethane (7.2 g, 76.2 mmol, 1.2 eq) in DCM (90 ml) wasstirred at 40° C. for overnight. After completion, the reaction waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by column chromatography (petroleumether:ethyl acetate=10:1) to give4-bromo-3-((ethoxymethoxy)methyl)benzonitrile (6.7 g, 32.4% yield overfour steps) as colorless liquid.

A solution of 4-bromo-3-((ethoxymethoxy)methyl)benzonitrile (5.1 g, 18.9mmol, 1.0 eq) and trimethyl borate (2.9 g, 28.4 mmol, 1.5 eq) in THF (75ml) was stirred at −78° C. and N₂ for 30 min. The n-BuLi (2.5 M inhexane, 9.1 ml, 22.6 mmol, 1.2 eq) added to the solution slowly at −78°C. and N₂, and the solution was warmed to room temperature. After 2 h, 6HCl (7 ml) was added to the solution. The solution was extracted withethyl acetate (3×20 mL) and the organic phase was washed by brine, driedwith Na₂SO₄, concentrated in vacuum to give light brown liquid. Methanol(2 ml) was added to the liquid and the white solid precipitated.Filtration to give1-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonitrile as a whitesolid (1.8 g, 62% yield).

1-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonitrile (210 mg, 1.32mmol, 1.0 eq) was added to HNO₃ (fuming, 1 ml) and H₂SO₄ (98%, 6 ml) at−45° C. The mixture was stirred for 2 h at −45° C., and warmed to roomtemperature. The mixture was poured into ice water (5 ml), and warmed toroom temperature to give yellow solution. The solution was dried withNa₂SO₄ and NaHCO₃ and concentrated in vacuum to give1-hydroxy-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonitrile (290mg, light yellow solid).

A solution of1-methyl-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbonitrile (crudeproduct, 260 mg, 1.27 mmol, 1.0 eq) and borane (THF solution, 1.0 M,6.35 ml, 6.35 mmol, 5.0 eq) in THF (20 ml) was stirred at 70° C. and N₂for 5 h. After completion, the reaction was quenched with methanol (10ml), washed with brine, dried over Na₂SO₄, filtered and concentrated invacuum give 5-(aminomethyl)-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (280mg) as yellow solid.

A solution of of 5-(aminomethyl)-6-nitrobenzo[c][1,2]oxaborol-1 (3H)-ol(crude product, 280 mg, 1.35 mmol, 1.0 eq), NaHCO₃ (435 mg, 5.4 mmol,4.0 eq) and BOC₂O (440 mg, 2.01 mmol, 1.5 eq) in water (20 mL) and THF(50 mL) was stirred at room temperature for 2 h. After completion, thereaction was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (petroleum ether, 1000 ml, then methanol 200 mL) to givetert-butyl((1-hydroxy-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)carbamate(320 mg) as a yellow solid.

A mixture of tert-butyl(1-hydroxy-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylcarbamate(crude product, 280 mg, 0.91 mmol, 1.0 eq) and Pd/C (28 mg, 10%) inethyl acetate (10 ml) was stirred at room temperature for 2 h. Then themixture was filtrated, concentrated in vacuum to give tert-butyl((6-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)carbamate(201 mg) as yellow liquid.

A mixture of tert-butyl(6-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylcarbamate(crude product, 201 mg, 0.72 mmol, 1.0 eq) and(1S,2R,3S,4S,6R,7R,8R,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.01,8]tetradecan-6-yl2-iodoacetate (423.0 mg, 0.86 mmol) in DMF (15 ml) was stirred at 80° C.for overnight. Then the mixture was concentrated in vacuum to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-((((l1-methyl)(l1-oxidanyl)boranyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate(420 mg) as brown liquid.

A mixture of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-((((l1-methyl)(l1-oxidanyl)boranyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate(crude product, 420 mg, 0.66 mmol, 1.0 eq) in TFA (1 mL) and DCM (3 mL)was stirred at room temperature for 1 h. Then the mixture wasconcentrated in vacuum to give the brown crude product and purified byprep-HPLC to provide(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(5-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate(50 mg, 6.9% yield from over 5 steps) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.98 (s, 1H), 7.22 (s, 1H), 6.82 (s, 1H), 6.00-6.08 (dd,1H), 5.56 (s, 1H), 5.53-5.57 (d, 1H), 4.88-5.02 (m, 3H), 4.43-4.54 (m,1H), 3.85-4.04 (m, 2H), 3.04 (s, 1H), 2.07-2.50 (m, 7H), 1.31-1.66 (m,13H), 1.05-1.24 (m, 4H), 0.50-0.60 (m, 3H), 0.22-0.37 (m, 3H). HPLCpurity: 100% (214 nm), 100% (254 nm); MS (ESI): mass calcd. forC₃₀H₄₃BN₂O₆ 538.32, m/z found 539.3 [M+H]⁺.

48.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate49.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To the solution of (2,4-dibromophenyl)methanol (10.0 g, 37.6 mmol) wasadded TBSCl (6.8 g, 45.1 mmol), imidazole (5.1 g, 75.2 mmol). Themixture was stirred at 40° C. overnight. After the reaction completed,the mixture was washed by water and DCM was removed under vacuo. Theresidue was purified by column chromatography on silica gel by elutionwith petroleum ether:ethyl acetate=50:1 to givetert-butyl(2,4-dibromobenzyloxy)dimethylsilane (14 g, yield 98%) as alight yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, 1H), 7.47 (m,2H), 4.69 (s, 2H), 0.94 (s, 9H), 0.15 (s, 6H).

To the solution of tert-butyl(2,4-dibromobenzyloxy)dimethylsilane (10.0g, 26.3 mmol) in dry THF (200 mL) was added LDA (2M, 26.3 mL) dropwiseat −78° C. The mixture was stirred at this temperature for 1 hour andDMF (10 mL) was added in one portion. The mixture was stirred at −78° C.for 1 hour and warmed to RT for additional 2 hours. After the reactioncompleted, the mixture was washed by water, extracted by ethyl acetate(200 mL×3). The organic layers were combined, dried over Na₂SO₄ andconcentrated to dryness, The residue was purified by columnchromatography on silica gel by elution with petroleum ether:ethylacetate=30:1 to2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)benzaldehyde (9.5 g,yield 89%). ¹H NMR (400 MHz, CDCl₃) δ 10.29 (s, 1H), 7.67 (m, 2H), 4.75(s, 2H), 0.99 (s, 9H), 0.17 (s, 6H).

To the solution of2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)benzaldehyde (7.0 g,17.1 mmol) was added NH₂OH.HCl (1.3 g, 18.9 mmol), NaOH (0.76 g, 18.9mmol). The mixture was stirred at RT for 1 hour. The solid was filtratedas the product (6.8 g, 94% yield), which was dried by oil pump and usedin the next step directly.

To the suspension of LAH (1.22 g, 32.2 mmol) in dry THF (50 mL) wasadded concentrated H₂SO₄ (1.58 g, 16.1 mmol) dropwise at 0° C. After theaddition, the mixture was stirred at 0° C. for 1 hour. The(E)-2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)benzaldehyde oxime(6.8 g, 16.1 mmol) was added to the mixture, and it was stirred at RTfor 2 hours. After the reaction completed, the mixture was quenched byalcohol and the solid was removed by filtration. The filtrate wasconcentrated to afford the(2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)methanamine(6.0 g, 91% yield) as a colorless oil. MS (ESI): mass calcd. forC₁₄H₂₃Br₂NOSi 408.99, m/z found 408.1 [M+H]⁺.

To the solution of(2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)methanamine(6.0 g, 14.7 mmol) in DCM (50 mL) was added Boc₂O (3.5 g, 16.1 mmol).The mixture was stirred at RT overnight. After the reaction completed,the mixture was concentrated to dryness and the residue was purified bycolumn chromatography on silica gel by elution with petroleumether:ethyl acetate=20:1 to afford tert-butyl2,6-dibromo-3-((tert-butyldimethylsilyloxy)methyl)benzylcarbamate (7.0g, yield 93%) as a white solid. MS (ESI): mass calcd. for C₁₉H₃₁Br₂NO₃Si509.04, m/z found 532.1 [M+Na]⁺.

To the solution of tert-butyl2-bromo-3-((tert-butyldimethylsilyloxy)methyl)-6-(diphenylmethyleneamino)benzylcarbamate(3.3 g, 6.5 mmol) in 30 mL toluene was added Pd₂(dba)₃ (0.60 g, 0.65mmol), Xantphos (0.75 g, 1.3 mmol), Cs₂CO₃ (6.3 g, 19.5 mmol),diphenylmethanimine (2.35 g, 13 mmol). The mixture was refluxed at 120°C. overnight. After the reaction completed, the mixture was purified bycolumn chromatography on silica gel by elution with petroleumether:ethyl acetate=20:1 to afford tert-butyl2-bromo-3-((tert-butyldimethylsilyloxy)methyl)-6-(diphenylmethyleneamino)benzylcarbamate(3.0 g, yield 75%) as a deep yellow oil. MS (ESI): mass calcd. forC₃₂H₄₁BrN₂O₃Si 610.20, m/z found 611.0 [M+H]⁺.

To the solution of tert-butyl2-bromo-3-((tert-butyldimethylsilyloxy)methyl)-6-(diphenylmethyleneamino)benzylcarbamate(2.4 g, 3.9 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.0 g, 7.8mmol) in dioxane (30 mL) was added Pd(OAc)₂ (87 mg, 0.39 mmol), PCy₃(218 mg, 0.78 mmol). The reaction mixture was stirred at 100° C.overnight under N₂. After the reaction completed, the solvent wasremoved under vacuo, the residue was purified by column chromatographyon silica gel by elution with petroleum ether:ethyl acetate=20:1 toafford tert-butyl3-((tert-butyldimethylsilyloxy)methyl)-6-(diphenylmethyleneamino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(970 mg, 38.5% yield) as a yellow oil. MS (ESI): mass calcd. forC₃₈H₅₃BrN₂O₅Si 656.38, m/z found 657.4 [M+H]⁺.

To the solution of tert-butyl3-((tert-butyldimethylsilyloxy)methyl)-6-(diphenylmethyleneamino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(970 mg, 1.5 mmol) in THF (20 mL) was added HCl (0.1 mL, 12 M) to keepthe PH of the mixture was 1. The reaction mixture was stirred at r.t.for 2 hours. The solid was filtrated and dried by oil pump as theproduct (300 mg, 63% yield). MS (ESI): mass calcd. for C₁₃H₁₉BN₂O₄278.14, m/z found 301.0 [M+Na]⁺.

To the solution of tert-butyl(6-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)methylcarbamate(105 mg, 0.38 mmol) in DMF (10 mL) was added Iodo-pleuromutilin (221 mg,0.45 mmol) and DIPEA (245 mg, 1.9 mmol). The reaction mixture wasstirred at 80° C. under N₂ overnight. The solvent was removed undervacuo and the residue was purified by prep-TLC (petroleum ether:ethylacetate=2:1) to afford the target product as brown oil((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate,80 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 1H), 7.05 (d, J=8.0Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 6.08 (m, 1H), 5.55 (d, J=8.0 Hz, 1H),4.93-5.08 (m, 2H), 4.83 (s, 1H), 4.33-4.50 (m, 3H), 3.89 (m, 1H), 3.40(m, 1H), 2.40 (m, 1H), 2.01-2.22 (m, 3H), 1.47-1.78 (m, 4H), 1.36 (s,9H), 1.22-1.27 (m, 4H), 1.00 (m, 4H), 0.75 (m, 3H), 0.64 (m, 3H). HPLCpurity: 100% (214 nm), 100% (254 nm); MS (ESI): mass calcd. forC₃₅H₅₁BN₂O₈ 638.37, m/z found 639.4 [M+H]⁺.

To the solution of above compound (82 mg, 0.13 mmol) in DCM (5 mL) wasadded TFA (1.5 mL). The mixture was stirred at r.t. for 2 hours. Thesolvent was removed under vacuo and the residue was purified byprep-HPLC (NH₄HCO₃ as buffer) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinateas white solid (30 mg, 43%). ¹H NMR (500 MHz, added one drop of con.HCl, DMSO-d₆) δ 8.2 (s, 3H), 7.19 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.5 Hz,1H), 6.08 (m, 1H), 5.55 (d, J=8.5 Hz, 2H), 4.89 (s, 4H), 4.21 (m, 2H),3.91 (m, 2H), 3.41 (m, 1H), 2.41 (s, 1H), 2.00-2.22 (m, 4H), 1.58-1.66(m, 2H), 1.48 (m, 1H), 1.24-1.39 (m, 7H), 0.97-1.03 (m, 4H), 0.80 (d,J=7.5 Hz, 3H), 0.64 (d, J=7.0 Hz, 3H). HPLC purity: 100% (214 nm), 100%(254 nm); MS (ESI): mass calcd. for C₃₀H₄₃BN₂O₆ 538.32, m/z found 539.4[M+H]⁺.

50.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To a CHCl₃ solution (120 mL) of 1-methyl-4-nitrobenzene (30.0 g, 218.8mmol), iron powder (3.6 g, 64.5 mmol) was added with mechanicallystirring. Then bromine (124.8 g, 40 mL, 780.9 mmol) was added slowlywhile raising temperature to 40° C. After addition of the bromine, themixture was heated to reflux for 48 h. After cooling, the solution waswashed with a saturated Na₂SO₃ solution, saturated Na₂CO₃ solution,brine, and dried over anhydrous Na₂SO₄. After the solvent was removed,the residue was purified by column chromatography to give the desiredproduct, giving 60 g (yield, 93%) of 1,3-dibromo-2-methyl-5-nitrobenzeneas yellow crystals.

To a solution of 1, 3-dibromo-2-methyl-5-nitrobenzene (60 g, 0.204 mol)in pyridine:DMF (1:2) (550 mL) was added CuCN (21.7 g, 0.245 mol). Thereaction mixture was heated to 140° C. overnight. After cooled to roomtemperature, ethyl acetate (500 mL) and ammonia water (400 mL) wereadded. The mixture was washed with water (300 mL×3). The solvent wasremoved and the residue was purified by silica gel column chromatographyusing petroleum ether:ethyl acetate=100:1 to give3-bromo-2-methyl-5-nitrobenzonitrile (15 g, yield: 30.6%) as a whitesolid.

To a solution of 3-bromo-2-methyl-5-nitrobenzonitrile (9.3 g, 38.6mmol), 4,4,4′,4′,5,5,5,5′-octamethyl-2,2,-bi(1,3,2-dioxaborolane) (11.78g, 46.3 mmol) and KOAc (7.75 g, 77.2 mmol) in 1,4-dioxane (200 ml) wasadded Pd(dppf)Cl₂ (3.5 g, 4.63 mmol) then the reaction mixture wasstirred at 90° C. under N₂ atmosphere overnight. The reaction mixturewas filtered through Celite and washed with EtOAc (200 mL). The filtratewas concentrated and the crude product was purified by silica gel columnto give2-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(9.64 g, 86% yield).

The mixture of2-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1 g, 3.5 mmol), NBS (740 mg, 4.2 mmol) and AIBN (60 mg, 0.35 mmol) inCCl₄ (50 ml) was refluxed overnight. The mixture was filtered and thefiltrate was concentrated to give2-(bromomethyl)-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(820 mg, 64.5% yield) as a white solid.

The mixture of2-methyl-5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1 g, 2.7 mmol) and NaOAc (1.07 g, 10.9 mmol) in DMF (15 mL) was stirredat 110° C. overnight, and then diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated under vacuum. The product(2-(acetoxymethyl)-3-cyano-5-nitrophenyl)boronic acid (600 mg, 83%yield) was directly used without further purification.

A solution of 2-(acetoxymethyl)-3-cyano-5-nitrophenylboronic acid (crudeproduct, 100 mg, 0.38 mmol) and borane (THF solution, 1.0 M, 3 ml, 3mmol, ) in THF (20 ml) was stirred at 70° C. and N₂ for 5 h. Aftercompletion, the reaction was quenched with methanol (10 ml), washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuum. The crudeproduct 4-(aminomethyl)-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol wasdirectly used in next step.

To a solution of 4-(aminomethyl)-6-nitrobenzo[c][1,2]oxaborol-1(3H)-ol(2.46 g, 0.0118 mol) and Boc₂O (3.09 g, 0.0142 mol) in THF (300 ml) wasadded Et₃N (2.38 g, 0.0236 mol) at 0° C. Then the mixture was stirred atr.t for 3 h, the reaction mixtures was concentrated under vacuum, andpurified by prep-HPLC to give 800 mg desired product.

A mixture of tert-butyl(1-hydroxy-6-nitro-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate(110 mg, 0.36 mmol, 1.0 eq) and Pd/C (28 mg, 10%) in MeOH (10 ml) wasstirred at room temperature for 2 h. Then the mixture was filtrated,concentrated in vacuum to give the desired product (89 mg) as yellowliquid.

A mixture of tert-butyl(6-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methylcarbamate(89 mg, 0.36 mmol, 1.0 eq) and SM-1 [(1S,2R,3S,4S,6R,7R,8R,14R)-4-ethenyl-3-hydroxy-2,4,7,14-tetramethyl-9-oxotricyclo[5.4.3.01,8]tetradecan-6-yl2-iodoacetate] (187 mg, 0.38 mmol) in DMF (15 ml) was stirred at 80° C.for overnight. Then the mixture was concentrated in vacuum to give thecrude product as brown liquid.

A mixture of (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(4-(((tert-butoxycarbonyl)amino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate(crude product, 420 mg, 0.66 mmol, 1.0 eq) in TFA (1 ml) and DCM (3 ml)was stirred at room temperature for 1 h. Then the mixture wasconcentrated in vacuum to give the brown crude product and purified byprep-HPLC to provide(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(4-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate,100 mg, yield 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.84(s, 1H), 6.71 (m, 2H), 6.09 (m, 1H), 5.92 (m, 1H), 5.54 (m, 1H),4.89-5.07 (m, 4H), 4.52 (d, 1H), 3.78 (m, 2H), 3.58 (s, 4H), 3.41 (m,1H), 2.41 (m, 1H), 2.02-2.09 (m, 5H), 1.34-1.67 (m, 7H), 1.24-1.28 (m,4H), 1.01 (s, 4H). HPLC purity: 98.4% (214 nm), 100% (254 nm); MS (ESI):mass calcd. for C₃₀H₄₃BN₂O₆ 538.32, m/z found 539.2 [M+H]⁺.

51.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To a solution of 6-amino-3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (177mg, 1 mmol) in DMF (3 mL) were added K₂CO₃ (276 mg, 2 mmol) andIodo-pleuromutilin (500 mg, 1 mmol). The reaction mixture was irradiatedunder microwave at 60° C. for 1 h. It was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate(600 mg, 29% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72(s, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.75-6.65 (m, 2H), 6.11-6.03 (m, 2H),5.55 (d, J=8.4 Hz, 1H), 5.04-4.93 (m, 2H), 4.50 (d, J=6 Hz, 1H),3.83-3.75 (m, 2H), 3.40 (t, J=7.8 Hz, 1H), 2.39 (s, 1H), 1.48-1.21 (m,21H), 0.80 (d, J=6.8 Hz, 3H), 0.63 (d, J=8.8 Hz, 3H). MS (ESI): masscalcd. For C₃₁H₄₄BNO₆ 537.33, m/z found 538.4 [M+H]⁺. HPLC: 98.8% (220nm), 99.5% (254 nm).

52.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate

To a solution of Iodo-pleuromutilin (1.4 g, 2.9 mmol, 1.0 eq.) and6-amino-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (600.0 mg, 2.9mmol, 1.0 eq.) in DMSO (10.00 mL) was added Ag₂SO₄ (2.70 g, 8.65 mmol,3.00 eq.). The mixture was stirred at 25° C. for 26 hours. HPLCindicated pleur-Iodide was consumed completely. The reaction mixture wasquenched by addition H₂O 150 mL, and filtered to give crude product,then diluted with DCM 100 mL and wished with brine 100 mL, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. Combined with ET3173-294,295-P1, we obtained 1.6 g desiredproduct(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo [c] [1,2] oxaborol-6-yl)amino) acetate (83%, purity), detected by HPLC.

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)amino)acetate (1.0 g, 1.8 mmol, 1.0 eq.) in AcOH (20.0 mL)was added Zn (920.2 mg, 14.1 mmol, 8.0 eq.). The mixture was stirred at25° C. for 4 hours. HPLC indicated(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)amino)acetate was consumed completely and a new peak was formed. The reactionmixture was filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Luna C18 100×30mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN]B %: 13%-53%, 12min]). The reaction mixture was concentrated under reduced pressure toremove CH₃CN, a drop of 1N HCl was added, then freeze-drying. (3aR, 4R,5R, 7S, 8S, 9R, 9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)amino)acetate(159.00 mg, 295.28 umol, 16.78% yield) was obtained as a yellow solid.(combined with ET3173-306-P1.)¹H NMR (DMSO-d₆, 400 MHz) δ 8.12 (br. s.,2H), 7.20 (d, J=7.9 Hz, 1H), 6.91 (br. s., 1H), 6.73 (dd, J=1.6, 8.4 Hz,1H), 6.08 (dd, J=11.2, 17.6 Hz, 1H), 5.55 (d, J=8.0 Hz, 1H), 5.19 (d,J=7.6 Hz, 1H), 5.04 (d, J=19.2 Hz, 1H), 4.95 (d, J=11.2 Hz, 1H), 3.80(d, J=13.2 Hz, 2H), 3.41 (d, J=5.6 Hz, 2H), 2.39 (br. s., 1H), 2.22-2.14(m, 1H), 2.12-1.98 (m, 3H), 1.69-1.57 (m, 2H), 1.54-1.39 (m, 2H),1.38-1.32 (m, 5H), 1.31-1.18 (m, 3H), 1.08-0.94 (m, 4H), 0.81 (d, J=6.4Hz, 3H), 0.64 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. For C₃₀H₄₄BClN₂O₆574.9, m/z found 539.5 [M+H]⁺. HPLC: 98.9% (220 nm), 100.0% (254 nm).

53.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborole-3,4′-piperidin]-6-yl)glycinate

To a stirred solution of 1-bromo-2-iodobenzene (25.6 g, 0.0753 mol, 1eq) in 90 mL of THF was added 1N i-PrMgCl (113 mL, 1.5 eq) under N₂ at−15˜20° C. After stirred for 2 hrs, tert-butyl4-oxopiperidine-1-carboxylate (15 g, 0.0903 mol, 1.2 eq) in 75 mL of THFwas added and the reaction was stirred overnight. The reaction wasquenched with saturated NH₄Cl₁ and the organic layer was separated. Theaqueous phase was extracted with ethyl acetate (250 mL×2). The organiclayers were combined, washed with water, brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was chromatographedon silica gel (25% ethyl acetate/petroleum ether) to give the tert-butyl4-(2-bromophenyl)-4-hydroxypiperidine-1-carboxylate (9.2 g, 40.3%) as awhite solid.

To a solution of tert-butyl4-(2-bromophenyl)-4-hydroxypiperidine-1-carboxylate (10 g, 0.0281 mol)in 120 mL of THF was added n-BuLi (2.5 M, 23.6 mL, 2.1 eq) under N₂ at−78° C. The reaction was stirred for 2 hrs and trimethyl borate (5.8 g,0.0561 mol, 2 eq) was added. The temperature was warm to RT graduallyand the reaction was stirred overnight. 1N HCl was added to adjust pH˜4,the organic layer was separated and the aqueous phase was extracted withethyl acetate for two times. The organic layers were combined, washedwith brine, died over anhydrous Na₂SO₄, filtered and concentrated. Thecrude product was chromatographed on silica gel (25% ethylacetate/petroleum ether) to give tert-butyl1-hydroxy-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1′-carboxylate(5.3 g, 62.3%) as a white solid.

tert-butyl1-hydroxy-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1′-carboxylate(4.0 g, 13.2 mmol, 1.0 eq) was added to HNO₃ (fuming, 0.7 mL) at −45° C.The mixture was stirred for 2 h at −45° C., and warmed to roomtemperature. The mixture was poured into ice water (5 mL), and theyellow crude product precipitated. After filtration, crude product6-nitro-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1-ol was obtained(2.1 g) as a light yellow solid.

A solution of of6-nitro-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1-ol (crude product,2.0 g, 8.06 mmol, 1.0 eq), NaHCO₃ (2.44 g, 29.04 mmol, 3.6 eq) and BOC₂O(2.11 g, 9.68 mmol, 1.2 eq) in water (15 mL) and THF (15 mL) was stirredat room temperature for 2 h. After completion, the reaction was washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by column chromatography (petroleum ether, 1000 mL,then methanol 200 mL) to give the crude product (1.02 g) as a yellowsolid.

A mixture of tert-butyl1-hydroxy-6-nitro-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1′-carboxylat(crude product, 1.0 g, 3.14 mmol, 1.0 eq) and Pd/C (100 mg, 10%) inethyl acetate (10 mL) was stirred at room temperature for 2 h. Then themixture was filtrated, concentrated in vacuum to give the crude product(250 mg) as yellow liquid.

A mixture of tert-butyl6-amino-1-hydroxy-1H-spiro[2,1-benzoxaborole-3,4′-piperidine]-1′-carboxylate(crude product, 240 mg, 0.65 mmol, 1.0 eq) and Iodo-pleuromutilin (722mg, 1.2 mmol) in DMF (15 mL) was stirred at 80° C. for overnight. Thenthe mixture was concentrated in vacuum to give the crude product (350mg) as brown liquid.

A mixture of above compound (350 mg, 1.1 mmol, 1.0 eq) in TFA (1 mL) andDCM (3 mL) was stirred at room temperature for 1 h. Then the mixture wasconcentrated in vacuum to give the brown crude product and purified byprep-HPLC to provide product((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1H-spiro[benzo[c][1,2]oxaborole-3,4′-piperidin]-6-yl)glycinate,26 mg, 1.7% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.12(s, 1H), 8.21-8.50 (m, 1H), 8.38-8.46 (m, 1H), 6.97-6.99 (d, 1H, J=8.0Hz), 6.83 (s, 1H), 6.71-6.73 (m, 1H), 6.03-6.10 (m, 2H), 5.45-5.56 (d,J=8.4 Hz, 1H), 4.92-5.04 (m, 2H), 4.50 (s, 1H), 3.77-3.81 (m, 3H),3.08-3.11 (m, 3H), 2.39 (s, 2H), 2.11-2.39 (m, 7H), 1.49-1.63 (m, 2H),1.34-1.45 (m, 3H), 1.21-1.30 (m, 5H), 1.02 (s, 4H), 0.79-0.81 (m, 3H),0.61-0.63 (m, 3H). HPLC purity: 100% (214 nm), 100% (254 nm); MS (ESI):mass calcd. for C₃₃H₄₇BN₂O₆ 578.35, m/z found 579.1 [M+H]⁺.

54.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)glycinate 55.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)carbamoyl)oxy)acetate

To a solution of 3,4-difluorobenzoic acid (8.0 g, 50.6 mmol, 1.00 eq.)in THF (400 mL) was added n-BuLi (2.5 M, 50.6 mL, 2.50 eq.), The mixturewas stirred at −78° C. for 2.5 hrs, then 12 (32.1 g, 126.5 mmol, 2.50eq.) in THF 100 mL was added, the mixture was stirred for another 0.5hr. TLC indicated the 3,4-difluorobenzoic acid was consumed completely,a new spot was formed. The reaction mixture was quenched by addition ofsaturation Na₂S₂O₃, and the mixture was extracted with EtOAc 1500 mL(500 mL×3), the combined organic layers were wished with brine 800 mL,drying over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. 3,4-Difluoro-2-iodobenzoic acid (11.0 g, 38.7 mmol,76.5% yield) was obtained as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ7.91 (ddd, J=2.0, 5.2, 8.8 Hz, 1H), 7.32-7.23 (m, 1H)

To a solution of 3,4-difluoro-2-iodobenzoic acid (13.0 g, 45.8 mmol,1.00 eq) in EtOH (100.0 mL) was added con.H₂SO₄ (18.4 g) 10 mL. Themixture was stirred at 90° C. for 16 hrs. TLC indicated3,4-difluoro-2-iodobenzoic acid was consumed completely, a new spot wasformed. The reaction mixture was concentrated under reduced pressure toremove EtOH. The residue was diluted with H₂O 100 mL and extracted withDCM 300 mL (100 mL×3). The combined organic layers were washed withbrine 200 mL, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5:1). Ethyl3,4-difluoro-2-iodobenzoate (14.0 g, 44.9 mmol, 98.0% yield) wasobtained as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ7.67 (ddd, J=2.0,5.0, 8.4 Hz, 1H), 7.25-7.18 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t,J=7.0 Hz, 3H).

To a solution of ethyl 3,4-difluoro-2-iodobenzoate (14.5 g, 46.5 mmol,1.0 eq.) and phenylmethanamine (7.5 g, 69.7 mmol, 1.5 eq.) in DMSO(150.0 mL) was added Et₃N (14.1 g, 139.4 mmol, 3.0 eq.). The mixture wasstirred at 100° C. for 16 hrs. TLC indicated ethyl3,4-difluoro-2-iodobenzoate was consumed completely and a new pot wasformed. The reaction mixture was quenched by addition H₂O 100 mL at 0°C., and then diluted with EtOAc 150 mL and extracted with EtOAc 600 mL(200 mL×3). The combined organic layers were washed with brine 240 mL(80 mL×3), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=50/1 to 10:1). ethyl4-(benzylamino)-3-fluoro-2-iodobenzoate (12.0 g, 30.1 mmol, 64.7% yield)was obtained as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.67 (d, J=8.4Hz, 1H), 7.41-7.29 (m, 5H), 6.58 (t, J=8.4 Hz, 1H), 4.82 (br. s., 1H),4.44 (d, J=5.6 Hz, 2H), 4.34 (q, J=7.0 Hz, 1H), 1.38 (t, J=7.0 Hz, 1H).

To a solution of ethyl 4-(benzylamino)-3-fluoro-2-iodobenzoate (4.5 g,11.3 mmol, 1.0 eq.) and Pin₂B₂ (28.6 g, 112.7 mmol, 10.0 eq.) in dioxane(150.0 mL) was added KOAc (3.3 g, 33.8 mmol, 3.0 eq.) and Pd (PPh₃)₂Cl₂(791.22 mg, 1.13 mmol, 0.1 eq.). The mixture was stirred at 120° C. for16 hrs. HPLC indicated ethyl 4-(benzylamino)-3-fluoro-2-iodobenzoate wasconsumed completely, main new formed peak as desired (Rf=4.2). Thereaction mixture was filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50/1). ethyl4-(benzylamino)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(6.0 g, crude) was obtained as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ7.62 (d, J=8.0 Hz, 1H), 7.38-7.28 (m, 5H), 6.57 (t, J=8.4 Hz, 1H), 4.75(br. s., 1H), 4.42 (d, J=5.6 Hz, 2H), 4.32 (q, J=7.4 Hz, 2H), 1.44 (s,12H).

To a solution of ethyl4-(benzylamino)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(5.0 g, 12.5 mmol, 1.0 eq.) in THF (20.0 mL) was added NaBH₄ (710.6 mg,18.8 mmol, 1.5 eq.) and CH₃OH (2.5 mmol, 0.2 eq.) at 0° C. The mixturewas stirred at 25° C. for 16 hours. HPLC indicated ethyl4-(benzylamino)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate was consumed completely. The reaction mixture was quenched byaddition H₂O (30 mL) dropwise, and then adjusted pH=6 and extracted withEtOAc 300 mL (100 mL×3). The combined organic layers were washed withbrine 100 mL, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue.6-(benzylamino)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (1.50 g, 5.83mmol, 46.57% yield) was obtained as a black solid. ¹H NMR (CDCl₃, 400MHz) δ 7.42-7.28 (m, 5H), 6.98-6.91 (m, 1H), 6.88-6.82 (m, 1H), 5.11 (s,1H), 5.02 (s, 2H), 4.45-4.34 (m, 3H).

To a solution of 6-(benzylamino)-7-fluorobenzo[c][1,2]oxaborol-1 (3H)-ol(100.0 mg, 389.0 umol, 1.0 eq.) in EtOAc (50.0 mL) was added Pd/C (100.0mg). The mixture was stirred at 25° C. for 4 hrs under H₂ atmosphere (50psi). The reaction mixture filtered and concentrated under reducedpressure to give a residue.6-amino-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (50.0 mg, 299.5 umol,77.0% yield) was obtained as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ7.00-6.90 (m, 2H), 5.07-5.00 (m, 2H), 4.83 (br. s., 1H), 3.73 (br. s.,2H).

To a solution of 6-amino-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (710.0mg, 4.3 mmol, 1.0 eq.) and Iodo-pleuromutilin (2.1 g, 4.3 mmol, 1.0 eq.)in DMSO (20.0 mL) was added Na₂CO₃ (901.50 mg, 8.50 mmol, 2.00 eq.). Themixture was stirred at 30° C. for 16 hrs. HPLC indicated6-amino-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol was consumed completely.The reaction mixture was quenched by addition H₂O 200 mL, and thenadjusted pH=6 (aq. 2N HCl). Filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna (2) C18 250×50 mm, 10 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 30%-60%, 20 min]).(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo [c][1,2] oxaborol-6-yl) amino)acetate (160.0 mg, 303.4 umol, 7.1% yield) was obtained as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.10 (s, 1H), 6.94 (d, J=7.9 Hz, 1H),6.73 (t, J=8.2 Hz, 1H), 6.09 (dd, J=11.0, 17.6 Hz, 1H), 5.63 (br. s.,1H), 5.55 (d, J=7.9 Hz, 1H), 5.08-4.96 (m, 2H), 4.86 (s, 2H), 4.49 (d,J=6.2 Hz, 1H), 3.91-3.81 (m, 2H), 3.38 (s, 1H), 2.38 (br. s., 1H),2.23-2.12 (m, 1H), 2.11-1.97 (m, 3H), 1.69-1.56 (m, 2H), 1.52-1.42 (m,2H), 1.32 (s, 3H), 1.29-1.16 (m, 3H), 1.05-0.96 (m, 3H), 0.80 (d, J=7.1Hz, 3H), 0.63 (d, J=6.6 Hz, 3H). MS (ESI): mass calcd. For C₂₉H₃₉BFNO₆527.4, m/z found 526.3 [M−H]⁻. HPLC: 96.7% (220 nm), 100.00% (254 nm).

At the same time,(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(((7-fluoro-1-hydroxy-1,3-dihydro benzo[c][1,2]oxaborol-6-yl)carbamoyl)oxy)acetate (170.0 mg, 280.4 umol, 6.2%yield) was obtained as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.55(br. s., 1H), 9.28 (s, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.29-7.12 (m, 1H),6.14 (dd, J=11.2, 18.0 Hz, 1H), 5.61 (d, J=8.0 Hz, 1H), 5.14-5.03 (m,2H), 4.97 (s, 2H), 4.60 (d, J=2.2 Hz, 2H), 4.52 (d, J=6.2 Hz, 1H), 3.43(t, J=6.0 Hz, 1H), 2.44 (s, 1H), 2.25-2.14 (m, 1H), 2.14-2.00 (m, 3H),1.74-1.57 (m, 2H), 1.53-1.20 (m, 8H), 1.13-0.95 (m, 4H), 0.83 (d, J=7.1Hz, 3H), 0.65 (d, J=6.6 Hz, 3H). MS (ESI): mass calcd. For C₃₀H₃₉BFNO₈571.3, m/z found 570.3 [M−H]⁻. HPLC: 99.4% (220 nm), 100% (254 nm).

56.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl) carbamate

To a suspension of 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-olhydrochloride salt (200 mg, 1.0 mmol) and K₂CO₃ (414 mg, 3.0 mmol) inDCM (20 mL) was added(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate (794 mg, 2.0 mmol) at 0° C. The mixture was stirred atroom temperature overnight. Then filtered, washed with DCM andconcentrated to give the crude. The residue was purified by prep-HPLC(column: Luna C18 100×30 mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v;B-ACN] B %: 40%-65%, 20 min]) to give the desired product(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate (225mg, yield 43.1%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.70 (t,J=5.8 Hz, 1H), 7.61 (s, 1H), 7.38-7.33 (m, 2H), 6.74 (dd, J=10.8, 17.6Hz, 1H), 5.53 (d, J=9.6 Hz, 1H), 5.24 (d, J=10.4 Hz, 1H), 4.96-4.90 (m,3H), 4.32-4.16 (m, 2H), 3.13-3.10 (m, 3H), 2.85 (d, J=6.4 Hz, 1H),2.36-2.33 (m, 1H), 2.07-1.61 (m, 5H), 1.41-1.38 (m, 2H), 1.18-1.01 (m,11H), 0.90 (d, J=6.4 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H). MS (ESI): masscalcd. for C₃₀H₄₂BNO₆ 523.3, m/z found 522.2 [M−H]⁻. HPLC: 99.0% (220nm), 100% (254 nm).

A solution of(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate (170mg, 0.33 mmol) in 1,4-dioxane (10 mL) cooled to 10° C. and treated witha half-saturated solution of zinc chloride in concd HCl (2 mL, 1 gZnCl₂) keeping the temperature<15 OC. The mixture was stirred at roomtemperature overnight. Then added water and extracted with EtOAc. Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate (51mg, yield 31%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) (7.58 (s, 1H),7.50 (t, J=6.0 Hz, 1H), 7.35-7.30 (m, 3H), 6.28-6.25 (dd, J=10.8, 17.6Hz, 1H), 5.44 (d, J=7.6 Hz, 1H), 5.09-4.94 (m, 4H), 4.18 (d, J=5.6 Hz,2H), 2.34 (s, 1H), 2.17-2.02 (m, 5H), 1.65-1.63 (m, 2H), 1.48-1.47 (m,2H), 1.30 (s, 3H), 1.35-1.09 (m, 4H), 1.05 (s, 3H), 0.80 (d, J=6.8 Hz,3H), 0.65 (d, J=5.6 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₄₀BNO₆ 509.2,m/z found 508.3 [M−H]⁻. HPLC: 99.3% (220 nm), 100% (254 nm).

57.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate

To a solution of TMP (20.4 g, 144.3 mmol, 1.3 eq.) in THF (150 mL) at−78° C. was slowly added n-BuLi (2.5 M, 57.7 mL, 1.3 eq.). The reactionvessel was transferred to a 0° C. ice bath for 1 hour and then recooledto −78° C. 2-fluoro-4-methyl-benzonitrile (15.0 g, 111.0 mmol, 1.0 eq.)as a solution in THF (20 mL) was then slowly added. The reaction mixturewas stirred at −78° C. for 2 hours, and then a solution of 12 (42.3 g,166.5 mmol, 1.5 eq.) in THF (10 mL) was slowly added and then thereaction mixture was allowed to warm to room temperature. 100 mL sodiumthiosulfate aqueous solution was added to the mixture, yellow solutionturn to colorless. The mixture was eluted with EtOAc 50 mL and separatedvia a separatory funnel. The aqueous phase was treated with EtOAc (50mL×3). The combined organic phase was washed with brine (100 mL×1),dried over Na₂SO₄ and concentrated under reduced pressure to give2-fluoro-3-iodo-4-methylbenzonitrile (16.0 g, crude) as a yellow solid.¹H NMR (CDCl₃, 400 MHz) δ 7.49 (dd, J=6.4, 7.8 Hz, 1H), 7.16 (d, J=7.8Hz, 1H), 2.57 (s, 3H).

2-fluoro-3-iodo-4-methyl-benzonitrile (17.0 g, 65.1 mmol, 1.0 eq.), NBS(17.4 g, 97.7 mmol, 1.5 eq.) and AIBN (1.1 g, 6.5 mmol, 0.1 eq.) in CCl₄(150 mL) were stirred at 80-90° C. for 24 hours. The mixture wasfiltered and concentrated to give crude product. The crude product waspurified by flash column chromatography (petroleum ether/EtOAc=10/1) togive 4-(bromomethyl)-2-fluoro-3-iodo-benzonitrile (4.5 g, 13.2 mmol,20.3% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (m, 1H),7.39 (d, J=9.2 Hz, 1H), 4.62 (s, 2H).

4-(bromomethyl)-2-fluoro-3-iodo-benzonitrile (4.5 g, 13.2 mmol, 1.0 eq.)and KOAc (3.9 g, 39.7 mmol, 3.0 eq.) in DMF (25 mL) were stirred at 15°C. for 1 hour. H₂O (50 mL) was added to the mixture. White solid wasprecipitated and filtered to give crude product, which was purified byflash chromatography (petroleum ether/EtOAc=1/1) to give4-cyano-3-fluoro-2-iodobenzyl acetate (3.5 g, 11.0 mmol, 82.9% yield) asa white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.62 (dd, J=6.2, 7.6 Hz, 1H),7.29 (dd, J=0.8, 7.6 Hz, 1H), 5.17 (s, 2H), 2.20 (s, 3H).

4-cyano-3-fluoro-2-iodobenzyl acetate (2.0 g, 6.3 mmol, 1.0 eq.),Pd(dppf)Cl₂ (367.0 mg, 501.6 umol, 0.08 eq.), KOAc (1.9 g, 18.8 mmol,3.0 eq.) and Pin₂B₂ (15.9 g, 62.7 mmol, 10.0 eq. in 1,4-dioxane (100 mL)were heated to 120° C. for 24 hours under nitrogen atmosphere. Two majorpeaks were detected. The mixture was filtered via celite, the solventwas concentrated in vacuo to give crude residue. The residue waspurified by flash chromatography (petroleum ether/EtOAc=10/1 to 2/1) togive product. Then the mixture was further purified by prep-HPLC((column: Phenomenex luna (2) C18 250×50 mm, 10 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 30%-60%, 30 min])). The organicsolvent was evaporated, and the aqueous phase was treated with DCM (100mL×3). The combined organic phase was dried over Na₂SO₄ and concentratedin vacuo to give4-cyano-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (600.0 mg, crude) as a yellow solid.

NaOH (150.4 mg, 3.8 mmol, 2.0 eq.) was added to a solution of4-cyano-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (600.0 mg, 1.9 mmol, 1.0 eq.) in MeOH (10 mL) and H₂O (20 mL).The mixture was stirred at 15° C. for 3 hours. HPLC and LCMS showedmajor as desired. The mixture was adjusted to pH<4 with 2N HCl aqueoussolution, and treated with DCM (50 mL×3). The combined organic phase wasdried over Na₂SO₄ and concentrated in vacuo to give crude7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonitrile(300.0 mg, crude) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.61 (s,1H), 7.99 (dd, J=6.2, 8.0 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 5.09 (s, 2H).

7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonitrile(300.0 mg, 1.7 mmol, 1.0 eq.) and Raney nickel (728.2 mg, 8.5 mmol, 5.0eq.) were stirred in EtOH (50 mL) under 10 Psi hydrogen atmosphere for 2hours. The mixture was filtered via a celite. The filtrate wasconcentrated to give6-(aminomethyl)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (250.0 mg, crude)as a white solid.

(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate (219.4 mg, 552.6 umol, 1.0 eq.) was added to asolution of 6-(aminomethyl)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol(100.0 mg, 552.6 umol, 1.0 eq.) and TEA (167.8 mg, 1.7 mmol, 3.0 eq.) inDCM (20 mL) at 15° C. The mixture was stirred at this temperature for 2hours. HPLC and LCMS showed major as desired. The reaction was quenchedby addition of water (30 mL). The mixture was treated with DCM (30mL×3). The combined organic phase was dried over Na₂SO₄ and concentratedin vacuo to give(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate(270.0 mg, crude) as white foam.

(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate(200.0 mg, 369.4 umol, 1.0 eq.) in ZnCl₂ saturated in HCl solution (14.6g, 106.8 mmol, 289.0 eq.) and THF (5 mL) were stirred at 15° C. for 0.5hour. 30 mL water was added to quench the reaction. The mixture wastreated with DCM (30 mL×3). The combined organic phase was dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified byprep-HPLC (column: Luna C18 100×30 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 43%-63%, 12 min]). The solvent wasconcentrated to about 20 mL solution left and dried over lyophilizer togive(3R,3aR,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbonochloridate(59.0 mg, 111.9 umol, 30.3% yield, 100% purity) as a white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 9.23 (s, 1H), 7.50 (t, J=6.0 Hz, 1H), 7.38 (t,J=7.2 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.20 (dd, J=11.2, 18.0 Hz, 1H),5.41 (d, J=8.8 Hz, 1H), 5.09-4.86 (m, 4H), 4.25-4.10 (m, 2H), 3.38 (d,J=5.6 Hz, 1H), 2.29 (s., 1H), 2.22-1.95 (m, 4H), 1.69-1.14 (m, 10H),1.06-0.88 (m, 4H), 0.78 (d, J=6.6 Hz, 3H), 0.62 (d, J=5.2 Hz, 3H). MS(ESI): mass calcd. for C₂₉H₃₉BFNO₆ 527.29, m/z found 526.3 [M−H]⁻. HPLC:100% (220 nm), 100% (254 nm).

58.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)carbamate

To a solution of(3R,3aS,4R,5R,7S,9R,9aR,12R)-5-hydroxy-3-methoxy-4,7,9,12-tetramethyl-7-vinyloctahydro-4,9a-propanocyclopenta[8]annulen-8(9H)-one(2.0 g, 6.0 mmol) and sodium cyanate (1.2 g, 18.0 mmol) in anhydroustoluene (20 mL) was added trifluroacetic acid (1 mL) slowly. The mixturewas stirred for 16 hrs at ambient temperature after which no STM wasdetected by HPLC analysis. Water (50 mL) was added to the mixture withstirring and organic layer was separated. The aqueous layer wasdiscarded and the toluene layer was concentrated under reduced pressureto a final volume of ˜5 mL. Heptane (25 mL) was added and the mixturewas stirred at 65° C. for 30 min. The mixture was cooled to 0° C. andstirred for 1 hr. The resulted slurry was filtered and washed with coldheptane, then dried under vacuum to give(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbamate (2.0 g, yield: 90.9%). ¹H NMR (CDCl₃, 400 MHz) δ 6.72 (dd,J=17.6, 10.8 Hz, 1H), 5.66 (d, J=10.0 Hz, 1H), 5.29 (d, J=10.8 Hz, 1H),5.02 (d, J=17.6 Hz, 1H), 4.60 (s, 2H), 3.47 (ddd, J=11.2, 8.0, 5.4 Hz,1H), 3.23 (s, 3H), 2.95 (q, J=6.4 Hz, 1H), 2.44 (dd, J=15.2, 10.0 Hz,1H), 2.27-2.15 (m, 1H), 2.07-1.93 (m, 2H), 1.79-1.54 (m, 4H), 1.50-1.40(m, 1H), 1.36-1.24 (m, 3H), 1.23-1.18 (m, 6H), 0.99 (d, J=6.4 Hz, 3H),0.88 (d, J=6.4 Hz, 3H).

A solution of(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-ylcarbamate (1.6 g, 4.2 mmol) in dry THF (30 mL) under a nitrogenatmosphere was cooled to −5 to 0° C., to the solution was added sodiumtert-butoxide (1.4 g, 12.6 mmol) over ˜10 min, maintaining the processtemperature below 5° C. The reaction mixture was stirred at 0° C. for 1hr. At the same time, the mixture of1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylic acid (754 mg,4.2 mmol) and CDI (1.4 g, 8.4 mmol) in THF (20 mL) was refluxed for 1hr, then added to the above solution dropwise and the mixture wasstirred overnight. Water was added, the mixture was extracted withEtOAc, washed with brine, dried and concentrated. The crude product waspurified by prep-HPLC to give(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)carbamate1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (0.4 g, ˜65%purity).

To a mixture of(3R,3aS,4R,5R,7S,9R,9aR,12R)-3-methoxy-4,7,9,12-tetramethyl-8-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)carbamate1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxylate (0.3 g, 0.56mmol) in dioxane (10 mL) was added saturated zinc chloride hydrochloricacid solution (10 mL) dropwise and the mixture was stirred at r.t for 30min. Water was added to quench the reaction. The mixture was extractedwith EtOAc, washed with brine, concentrated. The residue was purified byprep-HPLC (column: Luna C18 100×30 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %: 25%-60%, 20 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)carbamate (133mg, yield: 45.5%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.80 (s,1H), 9.35 (br.s., 1H), 8.19 (s, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H), 7.52(d, J=8.0 Hz, 1H), 6.27 (dd, J=17.6, 10.8 Hz, 1H), 5.59 (d, J=8.0 Hz,1H), 5.19-5.08 (m, 2H), 5.06 (s, 2H), 3.46 (d, J=5.6 Hz, 1H), 2.40 (s,1H), 2.29-2.02 (m, 4H), 1.75-1.49 (m, 4H), 1.45 (s, 3H), 1.43-1.22 (m,4H), 1.11 (s, 3H), 0.85 (d, J=6.4 Hz, 3H), 0.72 (d, J=6.4 Hz, 3H). MS(ESI): mass calcd. for C₂₉H₃₈BNO₇ 523.3, m/z found 522.2 [M−H]⁻. HPLC:100% (220 nm), 100% (254 nm).

59.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)glycinate

Tos-pleuromutilin (106 mg, 0.2 mmol),6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol (65 mg, 0.4 mmol) andK₂CO₃ (166 mg, 1.2 mmol) in 1 mL ACN was heated at 50° C. overnight.Main peak on LCMS is desired product. The crude was purified by prepHPLC (column: SunFire C18 OBD 100×30 mm, 5 μm) eluted with gradientwater/acetonitrile (0.1% TFA) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)glycinate (40mg, yield 39%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.60 (d, J=7.2 Hz, 3H), 0.78(d, J=6.8 Hz, 3H), 0.97 (br. s, 1H), 1.02 (d, 3H), 1.24 (d, 3H), 1.25(s, 1H), 1.4, (m, 3H), 1.61-1.9 (m, 3H), 2.02 (m, 2H), 2.07 (m, 2H), 2.4(s, 2H), 3.8 (m, 2H), 4.1 (m, 2H), 4.4 (br, s, 1H), 5.0-5.1 (m, 4H),5.59 (d, J=8.4 Hz, 1H), 6.06 (dd, J=17.8, 11.2 Hz, 1H), 7.5 (m, 2H),7.75 (s, 1H), 9.3 (br, s, 1H), 9.5 (br, s, 1H). MS (ESI): mass calcd.For C₃₀H₄₂BNO₆ 523.31, m/z found 524.3 [M+H]⁺. HPLC: 99.0% (220 nm).

60.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)glycinate

To a solution of Tos-Pleu (112 mg, 0.211 mmol), KI (6 mg, 0.035 mmol)and K₂CO₃ (48 mg, 0.352 mmol) in MeCN (3 mL) was added6-(aminomethyl)-3,3-dimethylbenzo[c][1,2] oxaborol-1(3H)-ol (40 mg,0.176 mmol). The reaction mixture was heated to reflux overnight. Afterremoved the solvent, the residue was purified by prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)glycinate(42 mg, yield 43%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.96(s, 1H), 7.57 (s, 1H), 7.38-7.32 (m, 2H), 6.24-6.17 (m, 1H), 5.62 (d,J=8.0 Hz, 1H), 5.12-5.06 (m, 2H), 4.53 (d, J=6.0 Hz, 1H), 3.71-3.68 (m,2H), 3.43-3.17 (m, 3H), 2.42 (s, 2H), 2.16-2.08 (m, 4H), 1.70-1.03 (m,21H), 0.83 (d, J=6.8 Hz, 3H), 0.62 (d, J=6.8 Hz, 3H). HPLC purity: 100%(214 nm), 100% (254 nm); MS (ESI): mass calcd. for C₃₂H₄₆BNO₆ 551.34,m/z found 552.2 [M+H]⁺.

61.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate 62.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((R)-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate63.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((S)-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate64.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfonyl)acetate

To a mixture of 2-bromo-4-fluorobenzaldehyde (30.0 g, 147.8 mmol, 1.0eq) and K₂CO₃ (32.7 g, 236.5 mmol, 1.6 eq) in DMF (350 mL) was added2-methylpropane-2-thiol (20.0 g, 221.7 mmol, 1.5 eq) at 15° C. under N₂.The mixture was stirred at 60° C. for 40 hrs. The reaction mixture waspoured into cold water (450 mL) and yellow solid precipitated. The solidwas filtered and washed with water twice, concentrated in vacuum toafford 2-bromo-4-(tert-butylthio)benzaldehyde (28.5 g, 104.3 mmol, 70.6%yield) as a yellow solid. ¹H NMR: (CDCl₃, 400 MHz) δ 10.35 (d, J=0.8 Hz,1H), 7.87-7.81 (m, 2H), 7.56 (dd, J=0.8, 8.0 Hz, 1H), 1.37 (s, 9H).

To a mixture of 2-bromo-4-(tert-butylthio)benzaldehyde (38.5 g, 140.9mmol, 1.0 eq) and BPD (178.9 g, 704.6 mmol, 5.0 eq) in dioxane (500 mL)was added KOAc (41.5 g, 422.8 mmol, 3.0 eq), Pd(dppf)Cl₂.CH₂Cl₂ (11.5 g,14.1 mmol, 0.1 eq) at 20° C. under N₂. The mixture was stirred at 80° C.for 16 hrs. To the reaction mixture was added activated carbon (500 mg),then filtered through celite and concentrated in vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50/1 to 24:1) to afford4-(tert-butylthio)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(46.00 g, crude) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 10.53 (s,1H), 7.98 (d, J=2.0 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (dd, J=2.0,8.0 Hz, 1H), 1.39 (s, 12H), 1.33 (s, 9H)

To a mixture of4-(tert-butylthio)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(4.6 g, 14.4 mmol, 1.0 eq) in DCM (300 mL) was added NaBH₄ (815.1 mg,21.5 mmol, 1.5 eq) at 0° C. under N₂. The mixture was stirred at 0° C.for 2 hrs under N₂. The reaction mixture was poured into water (100 mL)and acidified with aqueous HCl to pH=6. The aqueous phase was extractedwith ethyl acetate (30 mL×3). The combined organic phase was washed withsaturated brine (80 mL×2), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC (column:Phenomenex luna(2) C18 250×50 mm, 10 μm; liquid phase: [A-TFA/H₂O=0.075%v/v; B-ACN] B %: 30%-60%, 20 min) to give6-(tert-butylthio)benzo[c][1,2]oxaborol-1(3H)-ol (3.1 g, 14.0 mmol,97.2% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.26 (s, 1H),7.87 (d, J=2.0 Hz, 1H), 7.58 (dd, J=2.0, 8.0 Hz, 1H), 7.43 (d, J=8.0 Hz,1H), 5.02 (s, 2H), 1.23 (s, 9H).

To a mixture of AlCl₃ (5.7 g, 42.7 mmol, 5.0 eq) in toluene (300.0 mL)was added a solution of 6-(tert-butylthio)benzo[c][1,2]oxaborol-1(3H)-ol(1.9 g, 8.6 mmol, 1.0 eq) in DCM (50.0 mL) dropwise at −5° C. under N₂.The mixture was stirred at −5° C. for 4.5 hrs. The reaction mixture waspoured into water (450 mL) and acidified with 4 M HCl to pH=2 at 0° C.The aqueous phase was extracted with ethyl acetate (200 mL×3). Thecombined organic phase was washed with saturated brine (300 mL×2), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum to give aresidue. The residue was purified by prep-HPLC (column: Daiso 250×50 mm,10 um; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 25%-55%, 20min]) to give 6-mercaptobenzo[c][1,2]oxaborol-1(3H)-ol (0.3 g, 21.1%) asa white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.20 (s, 1H), 7.62 (s, 1H),7.39 (dd, J=1.2, 8.0 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 5.38 (br. s., 1H),4.92 (s, 2H).

A mixture of 6-mercaptobenzo[c][1,2]oxaborol-1 (3H)-ol (150.0 mg, 903.6umol, 1.0 eq), Tos-pleuromutilin (529.4 mg, 993.9 umol, 1.1 eq), K₂CO₃(312.2 mg, 2.2 mmol, 2.5 eq), KI (7.5 mg, 45.2 umol, 0.05 eq) in DMSO(20 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 40° C. for 4 hrs under N₂ atmosphere. The mixturewas poured into ice-water (50 mL), and then adjusted pH to 4-5, thesolid was precipitated, filtered, and the solid was washed with waterfor three times to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate (450.0mg, 854.7 umol, 94.6% yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.18 (s, 1H), 7.72 (s, 1H), 7.49 (dd, J=1.2, 8.0 Hz, 1H), 7.35 (d,J=8.0 Hz, 1H), 6.03-5.94 (m, 1H), 5.47 (d, J=8.8 Hz, 1H), 4.94 (s, 2H),4.90 (d, J=4.4 Hz, 1H), 4.47 (d, J=6.0 Hz, 1H), 3.79 (q, J=16.0 Hz, 2H),3.37 (s, 1H), 2.37-2.31 (m, 1H), 2.22-1.87 (m, 4H), 1.68-1.55 (m, 2H),1.50-1.14 (m, 7H), 1.08-0.93 (m, 6H), 0.79 (d, J=6.4 Hz, 3H), 0.55 (d,J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₉BO₆S 526.26, m/z found549.3 [M+Na]⁺. HPLC: 96.5% (220 nm), 96.8% (254 nm).

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate (200.0mg, 379.9 umol, 1.0 eq) in MeOH (10.0 mL) and H₂O (2.0 mL) was addedNaIO₄ (243.8 mg, 1.1 mmol, 3.0 eq). The mixture was stirred at 40° C.for 15 hrs. The reaction mixture was quenched by addition water 20 mL at0° C., and then diluted with EtOAc 10 mL and extracted with EtOAc (10mL×3). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Luna C18 100×30mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 40%-50%, 12min]), MeCN was removed under reduced pressure, the residue was driedunder freeze-drying to afford two isomers, randomly assigned as(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((R)-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate(80.0 mg, 147.5 umol, 38.8% yield) as a white solid. ¹H NMR (DMSO-d₆,400 MHz) δ 9.33 (s, 1H), 8.10 (s, 1H), 7.83 (dd, J=1.2, 8.0 Hz, 1H),7.60 (d, J=8.0 Hz, 1H), 6.03 (dd, J=11.6, 17.6 Hz, 1H), 5.47 (d, J=8.0Hz, 1H), 5.08-4.97 (m, 4H), 4.05-3.92 (q, J=14.4 Hz, 2H), 2.34 (s, 1H),2.23-1.86 (m, 5H), 1.69-1.12 (m, 10H), 1.09-0.93 (m, 5H), 0.80 (d, J=6.4Hz, 3H), 0.53 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₉BO₇S542.25, m/z found 541.2 [M−1]⁻. HPLC: Rt=2.89 min, 100% (220 nm), 100%(254 nm).

and(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((S)-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate(76.0 mg, 140.1 umol, 36.9% yield) as a white solid. ¹H NMR (DMSO-d₆,400 MHz) δ 9.39 (br. s., 1H), 8.0 (s, 1H), 7.81 (dd, J=1.2, 8.0 Hz, 1H),7.60 (d, J=8.0 Hz, 1H), 6.03 (dd, J=11.2, 18.0 Hz, 1H), 5.54 (d, J=8.4Hz, 1H), 5.09-4.98 (m, 4H), 4.11 (d, J=14.4 Hz, 1H), 3.79 (d, J=14.4 Hz,1H), 2.39 (s, 1H), 2.24-1.96 (m, 5H), 1.70-1.13 (m, 10H), 1.01 (m, 5H),0.81 (d, J=6.4 Hz, 3H), 0.65 (d, J=6.41 Hz, 3H). MS (ESI): mass calcd.for C₂₉H₃₉BO₇S 542.25, m/z found 541.2 [M−1]⁻. HPLC: Rt=2.94 min, 100%(220 nm), 100% (254 nm).

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate (400.0mg, 759.8 umol, 1.0 eq) in MeOH (20.0 mL) was added NaIO₄ (812.5 mg, 3.8mmol, 5.0 eq). The mixture was stirred at 60° C. for 72 hrs. Thereaction mixture was quenched by addition water 30 mL at 25° C., andthen diluted with EtOAc 10 mL and extracted with EtOAc (20 mL×3). Thecombined organic layers were washed with brine (100 mL×1), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Luna C18 100×30mm, 5 μm; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 33%-63%, 12min]), MeCN was removed under reduced pressure, the residue was driedunder freeze-drying to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfonyl)acetate(95.0 mg, 170.1 umol, 22.4% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.47 (s, 1H), 8.26 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.0 Hz, 1H), 5.97-5.86 (m, 1H), 5.38 (d, J=8.4 Hz, 1H), 5.04 (s, 2H),4.93 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.69 (d, J=15.2 Hz, 1H), 4.50 (d,J=15.2 Hz, 1H), 3.31 (d, J=6.0 Hz, 1H), 2.27 (s, 1H), 2.16-1.75 (m, 5H),1.61-1.14 (m, 6H), 1.12 (s, 3H), 0.92 (m, 5H), 0.74 (d, J=6.4 Hz, 3H),0.45 (d, J=7.2 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₉BO₈S 558.25, m/zfound 557.3 [M−1]⁻. HPLC: 99.8% (220 nm), 83.3% (254 nm).

65.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate66.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((S)-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate67.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((R)-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate

To a solution of 3,4-difluoro-2-iodobenzaldehyde (10.0 g, 37.3 mmol, 1.0eq) in DMSO (100.00 mL) was added Na₂S (4.1 g, 52.2 mmol, 1.4 eq) at 25°C. The mixture was stirred at 25° C. for 2 hours. To the mixture wasadded H₂O (100 mL) and solid precipitated. After filtration, thefiltrate was used directly in the next step.

To a mixture of 3-fluoro-2-iodo-4-mercaptobenzaldehyde (10.5 g, 37.2mmol, 1.0 eq) and Tos-pleuromutilin (19.8 g, 37.2 mmol, 1.0 eq) in THF(20 mL) was added Na₂CO₃ (11.8 g, 111.6 mmol, 3.0 eq) in one portion at25° C. The mixture was stirred at 25° C. for 2 hours. The mixture wasadded H₂O (100 mL). The aqueous phase was extracted with ethyl acetate(100 mL×3). The combined organic phase was washed with brine (20 mL×2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=20/1, 10/1, 5/1, 1/1) to afford product(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-fluoro-4-formyl-3-iodophenyl)thio)acetate (3.0 g, 4.7 mmol, 25.3%yield) as a light yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.02 (s,1H), 7.61 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.36 (dd, J=11.2,17.2 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 5.27 (d, J=11.6 Hz, 1H), 5.15 (d,J=17.2 Hz, 1H), 4.13 (d, J=7.6 Hz, 1H), 3.75-3.63 (m, 2H), 3.37-3.29 (m,1H), 2.37-1.98 (m, 4H), 1.81-1.32 (m, 9H), 1.21-1.07 (m, 6H), 0.87 (d,J=6.8 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H).

To a mixture of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-fluoro-4-formyl-3-iodophenyl) thio)acetate (1.5 g, 2.3 mmol, 1.0eq) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.9g, 23.3 mmol, 10.0 eq) in anhydrous dioxane (15 mL) was added KOAc(503.1 mg, 5.1 mmol, 2.2 eq) and Pd(PPh₃)₂Cl₂ (81.9 mg, 116.7 umol, 0.05eq) in one portion at 25° C. under N₂. The mixture was heated to 110° C.and stirred for 20 hours. The mixture was cooled to 25° C., thenfiltered and concentrated in vacuum to give crude product, which waspurified by silica gel chromatography (petroleum ether/ethylacetate=10/1, 3/1) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-fluoro-4-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thio)acetate (240.0 mg, 373.5 umol, 48.0% yield) as yellow solid.

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-fluoro-4-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thio)acetate(900.0 mg, 1.4 mmol, 1.0 eq) in DCM (50 mL) was added sodium;triacetoxyboranuide (593.4 mg, 2.8 mmol, 2.0 eq) at 25° C. The mixturewas stirred at 25° C. for 12 hours. HPLC and LCMS showed the reactionwas complete. H₂O (30 mL) was added the mixture. The aqueous layer wasextracted with DCM (30 mL×3). The combined organic layers were washedwith brine (20 mL) and dried over Na₂SO₄. After filtration via filterpaper, the organic layer was concentrated under reduced pressure toprovide crude product, which was purified by prep-HPLC (column: Waters Xbridge 150×25 5u; liquid phase: [A-10 mM NH₄HCO₃ in H₂O; B-ACN] B %:20%-50%, 12 min]). After prep-HPLC purification, the eluent wasconcentrated to remove organic solvent. The residual aqueous solutionwas lyophilized to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate(260.0 mg, 477.5 umol, 34.1% yield, 100% purity) as a white solid. ¹HNMR (DMSO-d₆, 400 MHz) δ 9.34 (s, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.22 (d,J=8.0 Hz, 1H), 6.04-5.94 (m, 1H), 5.46 (d, J=8.0 Hz, 1H), 5.00-4.88 (m,4H), 4.50 (d, J=6.0 Hz, 1H), 3.88-3.71 (m, 2H), 3.41-3.36 (m, 2H),2.38-2.35 (m, 1H), 2.24-1.87 (m, 4H), 1.69-1.55 (m, 2H), 1.50-1.40 (m,1H), 1.29 (s, 5H), 1.06-0.93 (m, 5H), 0.80 (d, J=6.8 Hz, 3H), 0.55 (d,J=6.8 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₈BFO₆S 544.25, m/z found543.2 [M−H]⁻. HPLC: 100% (220 nm), 100% (254 nm).

To a solution of(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)thio)acetate (160.0 mg, 293.8 umol, 1.0eq) in MeOH (5 mL) was added sodium; periodate (628.5 mg, 2.9 mmol,162.8 uL, 10.0 eq), then added H₂O (5 mL) at 25° C. The mixture washeated to 50° C. and stirred for 12 hours. The mixture was cooled to 25°C. The mixture was extracted with ethyl acetate (10 mL×3). The combinedorganic phase was washed with brine (10 mL×2), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuum. The residue was purified byprep-HPLC (column: Luna C8 100×30 mm, 5 μm; liquid phase:[A-TFA/H₂O=0.075% v/v; B-ACN] B %:35%-45%, 12 min]). After prep-HPLCpurification, the eluent was concentrated to remove organic solvent. Theresidual aqueous solution was lyophilized to give product(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((S)-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate(19.0 mg, 33.5 umol, 11.4% yield, 98.9% purity, sulfoxide chiral centerwas randomly assigned) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.89 (t, J=6.8 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 6.05 (dd, J=11.6, 17.6Hz, 1H), 5.57 (d, J=8.0 Hz, 1H), 5.13-4.97 (m, 4H), 4.20 (d, J=14.4 Hz,1H), 3.87 (d, J=14.4 Hz, 1H), 2.42 (br. s., 2H), 2.26-1.98 (m, 4H),1.73-1.58 (m, 2H), 1.56-1.47 (m, 1H), 1.39 (s, 4H), 1.34-1.20 (m, 3H),1.04 (s, 4H), 0.83 (d, J=6.4 Hz, 3H), 0.65 (d, J=6.8 Hz, 3H). MS (ESI):mass calcd. for C₂₉H₃₈BFO₇S 560.24, m/z found 559.3 [M−H]⁻. HPLC: 100%(220 nm), 100% (254 nm).

and (3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((R)-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfinyl)acetate(34.0 mg, 60.6 umol, 20.6% yield, 100% purity, sulfoxide chiral centerwas randomly assigned) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.89 (t, J=7.2 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 6.03 (dd, J=10.8, 18.4Hz, 1H), 5.48 (d, J=8.4 Hz, 1H), 5.12-4.95 (m, 4H), 4.19-3.96 (m, 2H),2.35 (d, J=9.2 Hz, 2H), 2.23-1.86 (m, 5H), 1.65 (d, J=16.0 Hz, 1H), 1.28(s, 6H), 1.05-0.91 (m, 6H), 0.81 (d, J=6.8 Hz, 3H), 0.59 (d, J=6.8 Hz,3H). MS (ESI): mass calcd. for C₂₉H₃₈BFO₇S 560.24, m/z found 559.2[M−H]⁻. HPLC: 98.9% (220 nm), 100% (254 nm).

68.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-7-yl)oxy)acetate

To a solution of 3,4-difluorobenzoic acid in THF (1 L) was added n-BuLi(2.5 M, 227.2 mL, 2.50 eq.). The mixture was stirred at −78° C. for 2.5hr, then 12 (144.1 g, 567.9 mmol, 2.5 eq.) (in 500 mL THF) was addeddrop-wise, The mixture was stirred at −78° C. for 0.5 hr. TLC indicated3,4-difluorobenzoic acid was consumed completely, one new spot formed.The reaction mixture was quenched by addition saturation Na₂S₂O₃ 500 mL,and then extracted with EtOAc 1500 mL (500 mL×3). The combined organiclayers were washed with brine 600 mL, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue.3,4-difluoro-2-iodobenzoic acid (45.0 g, 149.0 mmol, 65.6% yield) wasobtained as a white solid.

To a mixture of 3,4-difluoro-2-iodobenzoic acid (100.0 g, 352.1 mmol,1.0 eq.) in THF (1.0 L) was added BH₃-Me₂S (10 M, 105.6 mL, 3.0 eq.)dropwise at 0° C. under N₂. The mixture was stirred at 25° C. for 12hours. TLC (Petroleum ether:Ethyl acetate=2:1) showed the reaction wascompleted. The mixture was cooled to 0° C. and quenched with MeOH (100mL), H₂O (100 mL), adjusted pH˜4 with HCl (aq., 4N), concentrated underreduced pressure. The residue was poured into brine (100 mL) and stirredfor 5 min. The aqueous phase was extracted with ethyl acetate (200mL×3). The combined organic phase was washed with brine (100 mL×2),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to givethe (3,4-difluoro-2-iodophenyl)methanol (92.0 g, 340.7 mmol, 96.8%yield) as a yellow solid.

To a solution of (3,4-difluoro-2-iodophenyl)methanol (10.0 g, 37.0 mmol,1.0 eq.) and DMSO (5.8 g, 74.1 mmol, 5.8 mL, 2.0 eq.) in DCM (200.00 mL)was added (COCl)₂ (7.1 g, 55.6 mmol, 4.9 mL, 1.5 eq.) dropwise at −78°C. over a period of 30 min under N₂. The reaction mixture stirred at−78° C. for 0.5 hour. TLC (petroleum ether/ethyl acetate=3:1) showed thestarting material was consumed completely. The reaction was quenched byTEA (11.24 g, 111.1 mmol, 15.4 mL, 3.0 eq.) slowly and then extractedwith DCM (150 mL×3). The combined organic phase was washed with brine(50 mL×3), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the 3,4-difluoro-2-iodobenzaldehyde (5.0 g, 18.7 mmol,50.4% yield) as a white solid.

To a solution of 3,4-difluoro-2-iodobenzaldehyde (14.0 g, 52.2 mmol, 1.0eq.) and phenylmethanol (5.6 g, 52.2 mmol, 5.4 mL, 1.0 eq.) in DMF(150.0 mL) was added Cs₂CO₃ (22.1 g, 67.9 mmol, 1.3 eq.). The mixturewas stirred at 50° C. for 16 hours. HPLC indicated3,4-difluoro-2-iodobenzaldehyde was consumed completely. The crudeproduct 4-(benzyloxy)-3-fluoro-2-iodobenzaldehyde (crude) (dissolved inDMF) was used into the next step without further purification, abouthalf of the all was de-Bn (3-fluoro-4-hydroxy-2-iodobenzaldehyde).

To a solution of 3-fluoro-4-hydroxy-2-iodobenzaldehyde (mixed in4-(benzyloxy)-3-fluoro-2-iodobenzaldehyde) (12.0 g, 45.1 mmol, 1.0 eq.)and BnBr (11.5 g, 67.7 mmol, 8.0 mL, 1.5 eq.) in DMF (150.0 mL) wasadded Cs₂CO₃ (29.4 g, 90.2 mmol, 2.0 eq.). The mixture was stirred at50° C. for 5 hours. HPLC indicated main as desired product. The reactionmixture was quenched by addition H₂O 500 mL, and adjusted pH=6, solidwas dissolved out, filtered to give a desired.4-(benzyloxy)-3-fluoro-2-iodobenzaldehyde (15.0 g, 42.2 mmol, 93.3%yield) was obtained as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ9.98 (s, 1H), 7.69 (dd, J=1.6, 8.4 Hz, 1H), 7.44-7.33 (m, 5H), 7.07 (t,J=8.0 Hz, 1H), 5.25 (s, 2H)

To a solution of 4-(benzyloxy)-3-fluoro-2-iodobenzaldehyde) (1.0 g, 2.8mmol, 1.0 eq.) in THF (30.0 mL) was added NaBH₄ (106.2 mg, 2.8 mmol, 1.0eq.). The mixture was stirred at 25° C. for 10 min. TLC indicated4-(benzyloxy)-3-fluoro-2-iodobenzaldehyde) was consumed completely andone new spot formed. The reaction mixture was quenched by addition H₂O50 mL, and then adjusted pH=6 and extracted with ETOAc 150 mL (50 mL×3).The combined organic layers were washed with brine 100 mL, filtered andconcentrated under reduced pressure to give a residue.(4-(benzyloxy)-3-fluoro-2-iodophenyl) methanol (1.0 g, crude) was usedinto the next step without further purification. ¹H NMR (CDCl₃, 400 MHz)δ 7.42-7.36 (m, 5H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (t, J=8.4 Hz, 1H),5.15 (s, 2H), 4.66 (s, 2H)

To a solution of (4-(benzyloxy)-3-fluoro-2-iodophenyl) methanol (900.0mg, 2.5 mmol, 1.0 eq.) in DCM (30.0 mL) was added MsCl (862.6 mg, 7.5mmol, 582.8 uL, 3.0 eq.) and Et₃N (457.8 mg, 4.5 mmol, 626.2 uL, 1.8eq.). The mixture was stirred at 25° C. for 16 hours. TLC indicated(4-(benzyloxy)-3-fluoro-2-iodophenyl) methanol was consumed completely,and a new spot was formed. The reaction mixture was quenched by additionH₂O (50 mL), and then adjusted pH=7, extracted with EtOAc 150 mL (50mL×3). The combined organic layers were washed with brine 100 mL, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=20/1 to 10:1).1-(Benzyloxy)-4-(chloromethyl)-2-fluoro-3-iodobenzene (900.0 mg, 2.4mmol, 95.2% yield) was obtained as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.45-7.29 (m, 5H), 7.2 (d, J=8.8 Hz, 1H), 7.01-6.89 (m, 1H), 5.15(s, 2H), 4.68 (s, 2H)

To a solution of 1-(benzyloxy)-4-(chloromethyl)-2-fluoro-3-iodobenzene(200.0 mg, 531.0 umol, 1.0 eq.) in DMSO (2.0 mL) was added NaCN (78.0mg, 1.6 mmol, 3.0 eq.). The mixture was stirred at 50° C. for 4 hours.TLC indicated (4-(benzyloxy)-3-fluoro-2-iodophenyl) methanol wasconsumed completely. The reaction mixture was quenched by addition H₂O10 mL, and then extracted with EtOAc 60 mL (20 mL×3). The combinedorganic layers were washed with brine 40 mL, dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue.2-(4-(benzyloxy)-3-fluoro-2-iodophenyl)acetonitrile (190.0 mg, 517.5umol, 97.4% yield) was obtained as a white solid. ¹H NMR (CDCl₃, 400MHz) δ 7.44-7.35 (m, 5H), 7.22 (d, J=8.8 Hz, 1H), 7.01 (t, J=8.8 Hz,1H), 5.17 (s, 2H), 3.80 (s, 2H)

A solution of 2-(4-(benzyloxy)-3-fluoro-2-iodophenyl)acetonitrile (5.0g, 13.6 mmol, 1.0 eq.) in HCl/CH₃OH (10 M, 400.1 mL, 293.7 eq.) wasstirred at 70° C. for 48 hours. TLC indicated the reaction wascompletely. The reaction mixture was concentrated under reduced pressureto remove CH₃OH to give a crude product. methyl2-(3-fluoro-4-hydroxy-2-iodophenyl) acetate (5.0 g, crude, yellow oil)was used into the next step without further purification.

To a solution of methyl 2-(3-fluoro-4-hydroxy-2-iodophenyl) acetate(4.20 g, 13.55 mmol, 1.00 eq.) in DMF (20.00 mL) was added Cs₂CO₃ (8.8g, 27.1 mmol, 2.0 eq.) and bromomethylbenzene (2.8 g, 16.2 mmol, 1.9 mL,1.2 eq.). The mixture was stirred at 50° C. for 2 hours. TLC indicatedmethyl 2-(3-fluoro-4-hydroxy-2-iodophenyl) acetate was consumedcompletely. The reaction mixture was quenched by addition H₂O 50 mL, andthen extracted with EtOAc 600 mL (200 mL×3). The combined organic layerswere washed with brine 300 mL, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=50/1 to 10:1). methyl2-(4-(benzyloxy)-3-fluoro-2-iodophenyl)acetate (1.0 g, 2.5 mmol, 18.5%yield) was obtained as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ7.74-7.46 (m, 5H), 7.03-7.65 (m, 2H), 5.17 (s, 2H), 3.83 (s, 2H), 3.74(s, 3H)

To a solution of methyl methyl2-(4-(benzyloxy)-3-fluoro-2-iodophenyl)acetate (3.2 g, 8.0 mmol, 1.0eq.), AcOK (61.3 mg, 624.7 umol, 2.5 eq.) and Pin₂B₂ (20.3 g, 79.9 mmol,10.0 eq.) in dioxane (20.0 mL) was added Pd (PPh₃)₂Cl₂ (224.6 mg, 320.0umol, 0.04 eq.). The mixture was stirred at 120° C. for 16 hours. HPLCindicated the methyl 2-(4-(benzyloxy)-3-fluoro-2-iodophenyl) acetate wasconsumed completely. The reaction mixture was filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to5:1). methyl2-(4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.7 g, 6.7 mmol, 84.3% yield) was obtained as a brown oil. ¹HNMR (CDCl₃, 400 MHz) δ 7.45-7.31 (m, 5H), 6.95 (d, J=8.8 Hz, 1H), 6.87(t, J=8.8 Hz, 1H), 5.12 (s, 2H), 3.79 (s, 2H), 3.67 (s, 3H), 1.36 (s,12H)

To a solution of methyl2-(4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(1.0 g, 2.5 mmol, 1.0 eq.) in THF (10.0 mL) was added NaBH₄ (189.0 mg,5.0 mmol, 2.0 eq.). The mixture was stirred at 0° C. for 20 min. TLC,HPLC and LCMS indicated the reaction was completely. The reactionmixture was quenched by addition H₂O 50 mL, and then adjusted pH=6 andextracted with DCM 150 mL (50 mL×3). Dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex luna(2) C18 250×50 mm, 10 μm;liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %: 25%-55%, 20 min]).7-(benzyloxy)-8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-1-ol(290.0 mg, 1.0 mmol, 42.6% yield) was obtained as a white solid. MS(ESI): mass calcd. for C₁₅H₁₄BFO₃ 272.08, m/z found 271.0 [M−H]⁻. HPLC:100.00% (220 nm), 100.00% (254 nm). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.44 (s,1H), 7.47-7.29 (m, 5H), 7.24 (t, J=8.4 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H),5.2 (s, 2H), 4.00 (t, J=5.6 Hz, 2H), 2.78 (t, J=5.6 Hz, 2H)

To a solution of7-(benzyloxy)-8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-1-ol(200.0 mg, 735.1 umol, 1.0 eq) in EtOAc (40.0 mL) was added Pd/C (100.0mg). The mixture was stirred at 25° C. for 4 hours under H₂ atmosphere(50 psi). TLC indicated7-(benzyloxy)-8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-1-ol wasconsumed completely. The reaction mixture was filtered and concentratedunder reduced pressure to give a residue.8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinine-1,7-diol (100.0 mg,549.6 umol, 74.7% yield) was obtained as a white solid. MS (ESI): masscalcd. for C₃₀H₄₀BFO₇ 182.06, m/z found 180.9 [M−H]⁻. HPLC: 98.6% (220nm), 100.0% (254 nm). 1H NMR (DMSO-d₆, 400 MHz) δ 9.42 (s, 1H), 8.34 (s,1H), 6.95 (t, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 3.98 (t, J=5.6 Hz,1H), 2.74 (t, J=5.6 Hz, 1H)

To a solution of8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinine-1,7-diol (150.0 mg,824.4 umol, 1.0 eq.) and Tos-pleuromutilin (402.6 mg, 824.3 umol, 1.0eq.) in DMSO (20.0 mL) was added Na₂CO₃ (218.4 mg, 2.1 mmol, 2.5 eq.).The mixture was stirred at 25° C. for 16 hours. HPLC indicated the8-fluoro-3,4-dihydro-1H-benzo[c][1,2]oxaborinine-1,7-diol was consumedcompletely, a new peak formed. The reaction was quenched by addition ofH₂O 100 mL, and then adjusted pH=6, light yellow solid precipitated. Themixture was filtered and light yellow cake was washed cold water twice.The crude desired product was dissolved in THF (2 mL), then methyltert-butyl ether 30 mL and Petroleum ether gradient 30 mL was added,light yellow solid precipitated, filtered and the filtrate wasconcentrated under reduced pressure to give desired product.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-7-yl)oxy)acetate(110.0 mg, 202.8 umol, 24.6% yield) was obtained as a light yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz) δ. 8.41 (s, 1H) 7.20 (t, J=8.4 Hz, 1H),6.91 (d, J=8.4 Hz, 1H), 6.08 (dd, J=11.2, 17.6 Hz, 1H), 5.58 (d, J=8.0Hz, 1H), 5.08-4.97 (m, 3H), 4.82-4.65 (m, 2H), 3.98 (t, J=5.6 Hz, 2H),3.42-3.37 (m, 1H), 2.76 (t, J=5.6 Hz, 2H), 2.38-2.32 (m, 1H), 2.23-1.98(m, 4H), 1.72-1.19 (m, 8H), 1.08-0.94 (m, 5H), 0.80 (d, J=6.4 Hz, 3H),0.61 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₀BFO₇ 542.29, m/zfound 541.3 [M−H]⁻. HPLC: 95.7% (220 nm), 100.0% (254 nm).

69.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-7-yl)oxy)acetate

A mixture of Tos-pleuromutilin (294 mg, 0.55 mmol),3,4-dihydro-1H-benzo[c][1,2]oxaborinine-1,7-diol (90.7 mg, 0.55 mmol)and K₂CO₃ (228 mg, 1.65 mmol) in 5 mL of DMF was stirred at 50° C.overnight. Water was added and the mixture was adjust pH<4 with 2N HCl.The solid was filtered and the crude product was purified by Pre-HPLC(column: SunFire C18 OBD 100×30 mm, 5 μm) eluted with gradientwater/acetonitrile (0.1% TFA) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-7-yl)oxy)acetate asa white solid (85 mg, yield 29.5%). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.14 (s,1H), 7.07 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.06 (dd, J=11.2,17.6 Hz, 1H), 5.56 (d, J=8.0 Hz, 1H), 5.05-4.95 (m, 3H), 4.82-4.65 (m,2H), 3.99 (t, J=5.6 Hz, 2H), 3.42-3.37 (m, 1H), 2.74 (t, J=5.6 Hz, 2H),2.38-2.32 (m, 1H), 2.23-1.98 (m, 4H), 1.72-1.19 (m, 10H), 1.08-0.94 (m,4H), 0.77 (d, J=6.4 Hz, 3H), 0.60 (d, J=6.4 Hz, 3H). MS (ESI): masscalcd. for C₃₀H₄₁BO₇ 524.29, m/z found 523.2 [M−H]⁻. HPLC: 99.9% (220nm), 99.9% (254 nm).

70.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a solution of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(36.0 g, 106.5 mmol, 1.0 eq) in DCM (500 mL) was added trichloroborane(425 mL, 425.0 mmol, 4.0 eq) at 0° C. over a period of 30 mins under N₂.During which the temperature was maintained below 0° C. The reactionmixture was warmed to 25° C. over a period of 30 mins and stirred atroom temperature for 2 hours. The solvent was concentrated at roomtemperature and to the residue was add 200 mL water, green solidprecipitated and the mixture was filtered, the cake was dried to give(2-formyl-5-hydroxyphenyl)boronic acid (16.0 g, 96.4 mmol, 90.5% yield)as green solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.85 (s, 1H), 7.74 (d, J=8.4Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4, 8.4 Hz, 1H).

A solution of (2-formyl-5-hydroxyphenyl)boronic acid (200.0 mg, 1.2mmol, 1.0 eq) and tert-butyl N-aminocarbamate (159.3 mg, 1.2 mmol, 1.0eq) in EtOH (5 mL) was stirred at 25° C. for 12 hours. The mixture wasfiltered to give tert-butyl 1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (200.0 mg, 763.6 umol, 63.1% yield) aswhite solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.30 (s, 1H), 8.51 (s, 1H),8.02 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.19 (dd,J=2.4, 8.4 Hz, 1H), 1.57 (s, 9H).

A solution(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-iodoacetate (300.0 mg, 594.8 umol, 1.0 eq), tert-butyl1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (155.8 mg,594.8 umol, 1.00 eq) and K₂CO₃ (246.6 mg, 1.7 mmol, 3.0 eq) in DMF (10mL) was stirred at 50° C. for 2 hours. Water was added to the mixtureand acidified with 2N HCl (aq), white solid was precipitated andfiltered to give the crude product, which was purified by prep-TLC(petroleum ether/EtOAc=1/1) to give tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2, 8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(92.0 mg, 144.0 umol, 24.2% yield) as yellow solid.

A solution of tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (150.0 mg, 234.9 umol,1.0 Eq) and 2N HCl (5 mL) in MeOH (15 mL) was stirred at 20° C. for 2hours. The mixture was concentrated in reduced pressure. The aqueousphase was extracted with EtOAc (50 mL×3). The combined organic phase waswashed with saturated brine (50 mL×2), dried with anhydrous Na₂SO₄,filtered and concentrated to afford crude product, which was purified byprep-HPLC (Instrument: Gilson 281 semi-preparative HPLC system. Column:Synergi Max-RP C12 100×30 4 u. Mobile phase: A: TFA/H₂O=0.075% v/v; B:ACN Gradient: B % 24-100, 14.6 min. Flow rate: 25 ml/min. Monitorwavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo [d][1,2,3]diazaborinin-7-yl)oxy)acetate(20.0 mg, 37.1 umol, 15.8% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.86 (s, 1H), 7.96 (s, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.67 (d,J=2.4 Hz, 1H), 7.31 (dd, J=2.4, 8.4 Hz, 1H), 6.09 (dd, J=11.2, 17.8 Hz,1H), 5.60 (d, J=8.8 Hz, 1H), 5.12-4.96 (m, 2H), 4.89-4.76 (m, 2H), 3.32(d, J=5.6 Hz, 1H), 2.35 (s, 1H), 2.10-1.69 (m, 5H), 1.49-1.17 (m, 9H),1.11-0.97 (m, 3H), 0.83 (d, J=7.1 Hz, 3H), 0.65 (d, J=6.2 Hz, 3H). MS(ESI): mass calcd. for C₂₉H₃₉BN₂O₇ 538.3, m/z found 539.3 (M+H)⁺. HPLC:94.3% in 220 nm; 98.4% in 254 nm.

71. tert-butyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate72.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of Tos-pleuromutilin (200.0 mg, 375.5 umol, 1.0 eq),tert-butyl 1,7-dihydroxybenzo[d][1,2,3] diazaborinine-2(1H)-carboxylate(98.4 mg, 375.5 umol, 1.0 eq) and K₂CO₃ (155.7 mg, 1.1 mmol, 3.0 eq) inDMF (10 mL) was stirred at 50° C. for 1.5 hours. Water was added to themixture and acidified with 2N HCl (aq), white solid was precipitated andfiltered to give the crude product which was purified by prep-HPLC(Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10mM NH₄HCO₃ in H₂O; Gradient B: 55-100% CAN Column: Luna C18 100×30 mm, 5μm. Flow rate: 25 ml/min, 18 mins. Monitor wavelength: 220&254 nm).tert-butyl 1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(56.0 mg, 89.9 umol, 23.9% yield) was obtained as yellow solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.57 (s, 1H), 8.10 (s, 1H), 7.75 (d, J=8.2 Hz, 1H),7.47 (br. s., 1H), 7.38 (d, J=9.2 Hz, 1H), 6.09 (dd, J=11.0, 17.8 Hz,1H), 5.60 (d, J=8.6 Hz, 1H), 5.11-4.96 (m, 2H), 4.89 (d, J=6.0 Hz, 1H),4.53 (d, J=6.0 Hz, 1H), 2.41 (s, 1H), 2.26-1.96 (m, 4H), 1.65-1.58 (m,11H), 1.53-1.21 (m, 8H), 1.13-0.97 (m, 5H), 0.81 (d, J=6.8 Hz, 3H), 0.66(d, J=6.8 Hz, 3H). MS (ESI): mass calcd. for C₃₄H₄₇BN₂O₈ 622.3, m/zfound 639.4 (M+H₂O−H)⁻. HPLC: 96.4% in 220 nm; 96.5% in 254 nm.

To a mixture of tert-butyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(400.0 mg, 642.5 mmol, 1.0 eq) in DCM (30 mL) was added a solution ofhydrochloride in EtOA (5 mL, 4N) and the mixture was stirred for 2hours. The mixture was filtered and washed with DCM to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl) oxy)acetate(200.0 mg, 382.8 mmol, 59.6% yield) as yellow solid. ¹H NMR (DMSO-d₆,400 MHz) δ 9.90 (s, 1H), 7.96 (s, 1H), 7.75-7.64 (m, 2H), 7.31 (d, J=8.8Hz, 1H), 6.09 (dd, J=11.2, 17.8 Hz, 1H), 5.60 (d, J=8.2 Hz, 1H),5.13-4.95 (m, 2H), 4.89-4.74 (m, 2H), 3.41 (d, J=5.6 Hz, 1H), 2.41 (s,1H), 2.25-1.97 (m, 4H), 1.71-1.18 (m, 10H), 1.07-0.93 (m, 4H), 0.81 (d,J=6.8 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H). MS (ESI): mass calcd. forC₂₉H₃₉BN₂O₆ 522.3, m/z found 521.3 (M−H)⁻. HPLC: 99.7% in 220 nm; 100%in 254 nm.

73. tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate74.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (500.0 mg, 864.0 umol, 1.0 eq), tert-butyl1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (226.43 mg,864.02 umol, 1.0 eq) and K₂CO₃ (358.3 mg, 2.6 mmol, 3.0 eq) in DMF (20mL) was stirred at 50° C. for 1.5 hours. Water was added to the mixtureand acidified with 2N HCl (aq), white solid was precipitated andfiltered to give the crude product tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (400.0 mg, 598.3 umol, 69.3%yield) as yellow solid.

To a solution of tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(400.0 mg, 598.3 umol, 1.0 eq) and K₂CO₃ (825.0 mg, 5.9 mmol, 3.0 eq) inMeOH (50 mL) was stirred at 25° C. for 2 hours. The mixture was filteredand the solvent was evaporated to give the crude product, which wasfurther purified by prep-HPLC (Instrument: Gilson 281 semi-preparativeHPLC system. Column: Luna C18 100×30 mm, 5 μm. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 40-100, 16 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(66.0 mg, 103.0 umol, 17.2% yield) as white solid, ¹H NMR (DMSO-d₆, 400MHz) δ 8.57 (s, 1H), 8.11 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.48 (s, 1H),7.39 (d, J=8.8 Hz, 1H), 6.08 (dd, J=10.8, 17.6 Hz, 1H), 5.59 (d, J=6.8Hz, 1H), 5.13-4.83 (m, 5H), 4.68 (d, J=16.6 Hz, 1H), 2.28-1.94 (m, 3H),1.69 (m, 2H), 1.59 (s, 10H), 1.51-1.21 (m, 7H), 1.15-1.00 (m, 4H),0.95-0.78 (m, 3H), 0.69 (d, J=5.6 Hz, 3H). MS (ESI): mass calcd. forC₃₄H₄₆BFN₂O₈ 640.33, m/z found 656.8 (M+H₂O−H)⁻. HPLC: 93.1% in 220 nm;93.1% in 254 nm.

To a solution of tert-butyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(200.0 mg, 312.2 umol, 1.0 eq) in MeOH (25 mL) was added aqueous HCl(2N, 10 mL), the mixture was stirred at 25° C. for 2 hours. The mixturewas concentrated under reduced pressure to remove methanol. The aqueousphase was extracted with EtOAc (20 mL×3). The combined organic phase waswashed with saturated brine (20 mL×2), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuum to afford crude product, which waspurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Synergi Max-RP C12 100×30 4 u. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 20-100, 14.6 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(12.0 mg, 22.2 umol, 7.1% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ. 9.80 (s, 1H), 7.91 (s, 1H), 7.74-7.62 (m, 2H), 7.29 (d, J=8.0Hz, 1H), 6.07 (dd, J=11.0, 17.8 Hz, 1H), 5.58 (d, J=8.8 Hz, 1H), 5.09(dd, J=8.2, 17.6 Hz, 2H), 4.98 (d, J=10.0 Hz, 1H), 4.91-4.75 (m, 3H),3.34 (s, 1H), 2.61 (s, 1H), 2.22-1.74 (m, 5H), 1.46-1.16 (m, 7H), 1.04(s, 3H), 0.87-0.77 (m, 3H), 0.65 (d, J=6.0 Hz, 3H). MS (ESI): masscalcd. for C₂₉H₃₈BFN₂O₆ 540.3, m/z found 541.3 (M+H)⁺. HPLC: 93.6% in220 nm; 92.5% in 254 nm.

75.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A stirred mixture of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.0 g, 5.9 mmol) and methanesulfonohydrazide (0.06 g, 5.90mmol) in EtOH (20 mL) was stirred at 90° C. for 20 hrs. The mixture wasconcentrated to give a crude product which was purified by silica gelchromatography (petroleum ether:EtOAc=100:1 to 3:1) to give7-(benzyloxy)-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinin-1 (2H)-ol(1.0 g, 51.0% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.06(s, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.45-7.42 (m,2H), 7.41-7.35 (m, 4H), 7.16 (s, 1H), 5.20 (s, 2H), 3.33 (s, 3H).

To a stirred suspension of7-(benzyloxy)-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinin-1(2H)-ol(4.0 g, 12.1 mmol) in EtOAc (50 mL) was added Pd/C (1.0 g) under H₂. Theresulting mixture was stirred at r.t overnight. The mixture wasconcentrated to give2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol (2.5 g,86.0% yield) as a yellow solid.

A stirred mixture of2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol (100.0 mg,0.4 mmol) and Tos-pleuromutilin (222 mg, 0.4 mmol), K₂CO₃ (172.0 mg, 1.3mmol) in DMF (5 mL) was stirred at 50° C. for 12 hrs. The mixture wasdiluted with water and extracted with EtOAc The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated togive the crude product which was purified with prep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (68.0 mg, 26.9%). ¹H NMR (DMSO-d₆, 400MHz) δ 8.18 (s, 1H), 8.80-8.78 (m, 1H), 8.66 (s, 1H), 7.41-7.39 (m, 1H),6.12-6.08 (m, 1H), 5.12-5.08 (m, 1H), 5.01-4.98 (m, 2H), 4.88-4.86 (m,2H), 3.37 (s, 5H), 2.40 (s, 1H), 2.09-2.03 (m, 4H), 1.70-1.45 (m, 3H),1.33-1.25 (m, 8H), 1.05-0.95 (m, 4H), 0.82-0.80 (m, 3H), 0.65-0.64 (m,3H).

76.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

4-benzyloxy-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(8.0 g, 22.5 mmol, 1.0 eq) and NaIO₄ (24.0 g, 112.3 mmol, 5.0 eq) in THF(50 mL) and H₂O (50 mL) were stirred at 25° C. overnight, TLC shownmajor as desired, the mixture was filtered, the filtrate was treatedwith EtOAc. The organic layer was evaporated to give product(3-benzyloxy-2-fluoro-6-formyl-phenyl) boronic acid (6.0 g, crude) aswhite solid. ¹HNMR (DMSO-d₆, 400 MHz) δ 9.80 (d, J=2.8 Hz, 1H),8.27-8.09 (br. s., 2H), 7.80-7.66 (m, 1H), 7.53-7.21 (m, 6H), 5.30 (s,2H).

To a solution of (3-benzyloxy-2-fluoro-6-formyl-phenyl) boronic acid andMsNH₂NH₂ (6.0 g, 21.9 mmol, 1.0 eq) in EtOH (50 mL) was stirred at 50°C. for 12 hours. The mixture was filtered to give7-(benzyloxy)-8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinin-1(2H)-ol (4.0 g, 11.5 mmol, 52.5% yield) as yellow solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 7.90 (d, J=2.2 Hz, 1H), 7.62-7.28 (m, 6H), 5.27 (s,2H), 3.24 (s, 3H).

To a solution of7-(benzyloxy)-8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinin-1(2H)-ol (1.0 g, 2.9 mmol, 1.0 eq) in EtOAc (100 mL) was Pd/C (600.0 mg,10%) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (40 psi) at 20° C.for 2 hours. TLC (Petroleum ether:EtOAc=100:1 to 1) showed the startingmaterial was consumed completely. The reaction mixture was filtered andthe filtrate was concentrated to give8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol(700.0 mg, 2.7 mmol, 94.5% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 10.53 (s, 1H), 8.02 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.37-7.28(m, 2H), 3.33 (s, 3H).

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (600.0 mg, 1.0 mmol, 1.0 eq),8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol(267.5 mg, 1.0 mmol, 1.0 eq) and K₂CO₃ (429.9 mg, 3.1 mmol, 3.0 eq) inDMF (15 mL) was stirred at 50° C. for 2 hour. Water 50 mL was added tothe mixture and acidified with 2N HCl (aq.), white solid wasprecipitated and filtered to give the crude product(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(550.0 mg, crude) as yellow solid.

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(400.0 mg, 601.9 umol, 1.0 eq) and K₂CO₃ (414.0 mg, 3.0 mmol, 5.0 eq) inMeOH (50 mL) was stirred at 50° C. for 5 hours. Water 50 mL was added tothe mixture and acidified with 2N HCl (aq.), white solid wasprecipitated and filtered to give the crude product, which was purifiedby prep-HPLC (Instrument: Gilson 281 semi-preparative HPLC system.Column: Luna C18 100×30 mm, 5 μm. Mobile phase: A: 5 mM NH₄HCO₃ in H₂O;B: ACN Gradient: B % 15-100, 14.6 min. Flow rate: 20 ml/min. Monitorwavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(40.0 mg, 62.8 umol, 10.4% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.84 (br. s., 1H), 7.35 (br. s., 2H), 6.10 (dd, J=11.2, 17.8 Hz,1H), 5.58 (d, J=7.8 Hz, 1H), 5.13-4.99 (m, 2H), 4.99-4.82 (m, 2H), 4.69(d, J=6.2 Hz, 1H), 3.20 (s, 3H), 2.61 (s, 1H), 2.28-1.96 (m, 4H),1.87-1.49 (m, 3H), 1.44-1.18 (m, 6H), 1.07 (s, 3H), 0.84 (d, J=7.0 Hz,3H), 0.66 (d, J=6.8 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₃₉BF₂N₂OS636.2, m/z found 637.2 (M+H)⁺. HPLC: 98.4% in 220 nm; 100% in 254 nm.

77.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (400.0 mg, 729.0 umol, 1.0 eq),8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol(188.1 mg, 729.0 umol, 1.0 eq) and K₂CO₃ (302.3 mg, 2.2 mmol, 3.0 eq) inDMF (15 mL) was stirred at 50° C. for 2 hours. Water 50 mL was added tothe mixture and acidified with 2N HCl (aq.), white solid wasprecipitated and filtered to give the crude product, which was purifiedby prep-HPLC (Instrument: Gilson 281 semi-preparative HPLC system.Column: Luna C18 100×30 mm, 5 μm. Mobile phase: A: 5 mM NH₄HCO₃ in H₂O;B: ACN Gradient: B % 15-100, 14.6 min. Flow rate: 20 ml/min. Monitorwavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(30.0 mg, 47.3 umol, 6.5% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.75 (m, 1H), 7.28-7.21 (m, 2H), 6.11 (dd, J=11.2, 17.6 Hz, 1H),5.60 (d, J=8.0 Hz, 1H), 5.54 (d, J=6.0 Hz, 1H), 5.12 (d, J=17.6 Hz, 1H),5.00 (d, J=11.2 Hz, 1H), 4.88 (d, J=6.0 Hz, 2H), 4.65 (d, J=6.4 Hz, 1H),3.81-3.70 (m, 1H), 3.16 (s, 3H), 2.36 (s, 1H), 2.14-1.95 (m, 2H),1.82-1.72 (m, 2H), 1.41-1.16 (m, 9H), 1.07 (s, 3H), 0.83 (d, J=7.2 Hz,3H), 0.66 (d, J=6.0 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₀BFN₂O₉S634.3, m/z found 657.3 (M+Na)⁺. HPLC: 100% in 220 nm; 100% in 254 nm.

78.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-5-(2-chloroacetoxy)-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (500.0 mg, 906.0 umol, 1.0 eq) and KI (752.0 mg, 4.5mmol, 5.0 eq) in CH₃CN (50 mL) were stirred at 80° C. for 12 hours. Themixture was filtered, the organic layer was evaporated to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-5-(2-chloroacetoxy)-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl2,2-dichloroacetate (520.0 mg, 808.3 umol, 89.2% yield). ¹H NMR (CDCl₃,400 MHz) δ. 8.15 (s, 1H), 6.25 (dd, J=11.2, 17.6 Hz, 1H), 6.01 (s, 1H),5.66 (d, J=7.8 Hz, 1H), 5.38-5.18 (m, 2H), 5.10 (t, J=9.0 Hz, 1H), 4.95(d, J=6.4 Hz, 1H), 3.71-3.56 (m, 2H), 2.57-2.40 (m, 2H), 2.22-2.08 (m,2H), 2.02-1.88 (m, 2H), 1.68-1.37 (m, 6H), 1.09 (s, 3H), 0.87 (d, J=7.0Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-8-(formyloxy)-5-(2-iodoacetoxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-2-yl,2-dichloroacetate(500.0 mg, 777.2 umol, 1.00 eq) and K₂CO₃ (322.3 mg, 2.3 mmol, 3.0 eq)in MeOH (50 mL) was stirred at room temperature for 12 hours. Themixture was filtered and the solvent was evaporated to give the crudeproduct(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-iodoacetate (400.0 mg, crude) as yellow solid, and used directly.

A solution of(2S,3aR,4R,5R,7S,8S,9S,9aS,12R)-2-hydroxy-4,7,8,9,12-pentamethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (110.0 mg, 200.4 umol, 1.0 eq),2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (35.2 mg, 200.48 umol,1.0 eq) and K₂CO₃ (83.1 mg, 601.4 umol, 3.0 eq) in DMF (5 mL) wasstirred at 50° C. for 2 hours. Water was added and adjusted pH<4 with 2Naq. HCl white solid was precipitated and filtered to give the crudeproduct, which was purified by prep-HPLC (Instrument: Gilson 281semi-preparative HPLC system. Column: Luna C18 100×30 mm, 5 μm. Mobilephase: A: TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 30-100, 14.6 min.Flow rate: 25 ml/min. Monitor wavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(25.0 mg, 45.3 umol, 22.6% yield) as yellow solid, ¹H NMR (DMSO-d₆, 400MHz) δ 8.19 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.40 (d,J=6.4 Hz, 1H), 6.09 (dd, J=11.2, 17.6 Hz, 1H), 5.60 (d, J=8.0 Hz, 1H),5.11-4.81 (m, 4H), 3.75 (t, J=8.4 Hz, 1H), 3.48 (s, 3H), 3.31 (m, 1H),2.35 (s, 1H), 2.07 (m, 2H), 1.87-1.70 (m, 2H), 1.51-1.18 (m, 7H),1.10-0.99 (m, 4H), 0.83 (d, J=7.0 Hz, 3H), 0.64 (d, J=6.8 Hz, 3H). MS(ESI): mass calcd. for C₃₀H₄₁BN₂O₉S 616.3, m/z found 632.8 (M+H₂O−H)⁻.HPLC: 99.0% in 220 nm; 98.8% in 254 nm.

79.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (350.0 mg, 605.0 umol),2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol (145.0 mg,605.0 umol) and potassium carbonate (250.0 mg, 1.8 mmol) in DMF (25.0mL) were stirred at 50° C. for 2 hours, water was added, the mixture wasfiltered to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (300.0 mg, crude). Potassium carbonate (192.0 mg, 1.4 mmol)was added to(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(0.3 g, 464.0 umol) in MeOH (20.0 mL) and THF (20.0 mL). The mixture wasstirred at 50° C. for 2 hours, the mixture was adjusted pH<4 with 2NHCl. Solvent was evaporated, the crude product was purified by prep-HPLCto give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(46.0 mg, 12.0% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.19 (s, 1H), 7.80(d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 6.08 (dd,J=11.4, 18.1 Hz, 1H), 5.58 (d, J=9.0 Hz, 1H), 5.09 (d, J=17.6 Hz, 2H),5.00 (d, J=11.8 Hz, 1H), 4.95 (br. s., 1H), 4.90 (d, J=10.4 Hz, 2H),3.37 (s, 3H), 3.34 (br. s., 1H), 2.62 (br. s., 1H), 2.25-1.93 (m, 4H),1.81 (d, J=14.8 Hz, 1H), 1.50-1.18 (m, 9H), 1.05 (s, 3H), 0.84 (d, J=7.2Hz, 3H), 0.67 (d, J=6.0 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₀BFN₂OS618.26, m/z found 635.3 [M+H₂O−H]⁻. HPLC: 95.0% (220 nm), 96.5% (254nm).

80.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate81.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of Tos-pleuromutilin (250.0 mg, 469.3 umol, 1.0 eq),8-fluoro-2-(methylsulfonyl)benzo[d][1,2,3]diazaborinine-1,7(2H)-diol(121.1 mg, 469.3 umol, 1.0 eq) and K₂CO₃ (194.6 mg, 1.4 mmol, 3.0 eq) inDMF (15 mL) was stirred at 50° C. for 2 hours. Water 50 mL was added tothe mixture and acidified with 2N HCl (aq.), white solid wasprecipitated and filtered to give the crude product, which was furtherpurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Synergi Max-RP C12 100×30 4u. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 35-100, 14.6 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give two products:

(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-(methylsulfonyl)-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(16.0 mg, 25.9 umol, 5.5% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400MHz) δ 7.90 (s, 1H), 7.50-7.28 (m, 2H), 6.13 (m, 1H), 5.61 (s, 1H),5.19-4.84 (m, 3H), 4.54 (s, 1H), 3.24 (s, 3H), 2.41 (s, 1H), 2.07 (m,4H), 1.73-1.19 (m, 11H), 1.06 (m, 4H), 0.82 (d., J=6.8 Hz, 3H), 0.65 (d,J=6.8 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₀BFN₂OS 618.3, m/z found619.2 (M+H)⁺. HPLC: 95.2% in 220 nm; 98.0% in 254 nm.

and(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(26.0 mg, 52.2 umol, 11.1% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.64 (s, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.55-7.40 (m, 2H), 6.10(dd, J=11.2, 17.8 Hz, 1H), 5.60 (d, J=8.4 Hz, 1H), 5.11-4.97 (m, 2H),4.94 (d, J=3.2 Hz, 1H), 3.41 (d, J=6.2 Hz, 1H), 2.40 (s, 1H), 2.27-1.97(m, 4H), 1.73-1.20 (m, 11H), 1.04 (s, 4H), 0.81 (d, J=7.0 Hz, 3H), 0.64(d, J=7.0 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₈BFN₂O₆ 540.3, m/zfound 541.3 (M+H)⁺. HPLC: 96.7% in 220 nm; 97.9% in 254 nm.

82.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a solution of(2S,3aR,4R,5R,7S,8S,9S,9aS,12R)-2-hydroxy-4,7,8,9,12-pentamethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (110.0 mg, 200.4 umol, 1.0 eq),2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (35.2 mg, 200.48 umol,1.0 eq) and K₂CO₃ (83.1 mg, 601.4 umol, 3.0 eq) in DMF (5 mL) wasstirred at 50° C. for 2 hours. Water (20 mL) was added and the solutionwas acidified to pH=4 with 2N aq. HCl acid, white solid was precipitatedand the mixture was filtered to give the crude product, which waspurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Luna C18 100×30 mm, 5 μm. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 30-100, 14.6 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(25.0 mg, 45.3 umol, 22.6% yield) as white solid, ¹H NMR (DMSO-d₆, 400MHz) δ 7.91 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H),7.28 (dd, J=2.4, 8.8 Hz, 1H), 6.09 (dd, J=11.2, 17.6 Hz, 1H), 5.60 (d,J=8.0 Hz, 1H), 5.10 (d, J=17.6 Hz, 1H), 5.00 (d, J=11.2 Hz, 1H), 4.81(t, J=15.2 Hz, 2H), 3.75 (t, J=8.4 Hz, 1H), 3.48 (s, 3H), 3.31 (d, J=5.6Hz, 1H), 2.35 (s, 1H), 2.07-1.95 (m, 2H), 1.87-1.70 (m, 2H), 1.51-1.18(m, 9H), 1.04 (s, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.64 (d, J=6.2 Hz, 3H).MS (ESI): mass calcd. for C₃₀H₄₁BN₂O₇ 552.3, m/z found 553.3 (M+H)⁺.HPLC: 98.9% in 220 nm; 97.7% in 254 nm.

83.(3aR,4R,5R,7S,8S,9aS,12R)-8-hydroxy-4,7,12-trimethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a stirred solution of4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (6.0 g, 17.7 mmol) in EtOH (300 mL) was added themethylhydrazine hydrochloride (1.3 g, 17.7 mmol). The mixture wasstirred at 50° C. for 12 hours. The mixture was cooled and the solid wasfiltered, washed by EtOH.7-(benzyloxy)-2-methylbenzo[d][1,2,3]diazaborinin-1(2H)-ol was obtainedwithout further purification (3.6 g, 69.0% yield). ¹H NMR (DMSO-d₆, 400MHz) δ 7.94 (s, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H),7.41-7.34 (m, 5H), 5.20 (s, 2H), 3.49 (s, 3H).

To a stirred solution of7-(benzyloxy)-2-methylbenzo[d][1,2,3]diazaborinin-1(2H)-ol (2.6 g, 9.8mmol) in EtOH (30 mL) was added Pd/C (1 g) and the mixture was stirredat 50 psi under hydrogen atmosphere for 12 hours. The mixture wasfiltered through celite and the filtrate was concentrated in vacuo togive 2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (1.1 g, 64.0%yield) as white solid without further purification. ¹H NMR (DMSO-d₆, 400MHz) δ 7.93 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.16 (m, 1H),3.47 (s, 3H).

Tos-pleuromutilin (500.0 mg, 938.0 umol),2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (165.0 mg, 938.0 umol)and potassium carbonate (389.0 mg, 2.8 mmol) in DMF with cata. amountpotassium iodide were heated to 50° C. for 4 hours, water was added andadjusted pH<4 with 2N aq. HCl white solid was precipitated and filteredto give to give crude product which was purified by prep-HPLC(Instrument: Gilson 281 semi-preparative HPLC system. Column: Luna C18100×30 mm, 5 μm. Mobile phase: A: TFA/H₂O=0.075% v/v; B: ACN Gradient: B% 35-100, 16 min. Flow rate: 20 ml/min. Monitor wavelength: 220&254 nm)to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (121.0 mg, 74.0%) as white solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.31 (s, 1H), 7.90 (s, 1H), 7.76 (br. s., 1H), 7.68(d, J=8.8 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 6.10 (dd, J=10.8, 17.2 Hz,1H), 5.60 (d, J=7.8 Hz, 1H), 5.14-4.93 (m, 2H), 4.88-4.71 (m, 2H), 4.54(d, J=5.8 Hz, 1H), 3.47 (s, 2H), 3.41 (br. s., 1H), 3.07 (s, 3H), 2.41(br. s., 1H), 2.26-1.95 (m, 4H), 1.73-0.92 (m, 10H), 0.90-0.76 (m, 3H),0.63 (d, J=6.0 Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₁BN₂O₆ 536.3, m/zfound 535.3 (M−H)⁻. HPLC: 90.7% in 220 nm; 93.3% in 254 nm.

84.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a mixture of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy) acetate (157.0 mg, 271.3 umol, 1.0 eq) and2-methylbenzo[d][1,2,3]diazaborinine-1, 7(2H)-diol (50.1 mg, 284.87umol, 1.1 eq) in DMF (5 mL) was added K₂CO₃ (75.0 mg, 542.6 umol, 2.0eq) in one portion at r.t. under N₂. The mixture was stirred at 50-60°C. for 4.5 hours. The mixture was cooled to 25° C. and poured intoice-water. The mixture was acidified with HCl (aq) and filtered to givethe crude(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (100.0 mg, 120.1 umol, 44.3%yield, 70.0% purity) as white solid.

To a mixture of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (100.0 mg, 120.1 umol, 1.0 eq)in MeOH (10 mL) was added K₂CO₃ (166.1 mg, 1.2 mmol, 10.0 eq) in oneportion at room temperature under N₂. The mixture was stirred at 50° C.for 10 hours. The mixture was cooled to 25° C., and concentrated inreduced pressure. The residue was poured into ice-water and extractedwith EtOAc (30 mL×3). Dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by prep-HPLC(Instrument: Gilson 281 semi-preparative HPLC system. Column: Luna C18100×30 mm, 5 μm. Mobile phase: A: TFA/H₂O=0.075% v/v; B: ACN Gradient: B% 30-100, 16 min. Flow rate: 20 ml/min. Monitor wavelength: 220&254 nm)to afford(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(15.0 mg, 27.1 umol, 22.5% yield) as light yellow solid. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.31 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 7.68 (d,J=8.2 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.03-6.14 (m, 1H), 5.50-5.62 (m,1H), 4.94-5.14 (m, 3H), 4.63-4.89 (m, 4H), 3.47 (s, 3H), 2.41 (s, 1H),1.18-1.43 (m, 9H), 1.04 (br.s., 3H), 0.82 (d, J=7.0 Hz, 3H), 0.65 (m,3H). MS (ESI): mass calcd. for C₃₀H₄₀BFN₂O₆ 554.3, m/z found 553.3(M−H)⁻. HPLC: 95.3% in 220 nm; 94.3% in 254 nm.

85.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(500.0 mg, 1.4 mmol) and methylhydrazine hydrochloride acid (140.0 mg,1.7 mmol) in EtOH (10 mL) was stirred at 50° C. for 2 hours. Aftercooled to room temperature, the mixture was filtered to give7-(benzyloxy)-8-fluoro-2-methylbenzo[d][1,2,3]diazaborinin-1(2H)-ol(340.0 mg, 85.5% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.92(d, J=2.8 Hz, 1H), 7.70-7.63 (m, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.51-7.46(m, 2H), 7.44-7.32 (m, 3H), 5.29 (s, 2H), 3.48 (s, 3H).

To a solution of7-(benzyloxy)-8-fluoro-2-methylbenzo[d][1,2,3]diazaborinin-1(2H)-ol(200.0 mg, 704.0 umol) in EtOAc (20 mL) was added Pd—C (10%, 2 g) underN₂. The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (40 psi) at 20° C. for 2 hours.The reaction mixture was filtered and the filter was concentrated togive 8-fluoro-2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (29.0mg, 21.2% yield) as white solid.

A solution of Tos-pleuromutilin (79.6 mg, 149.5 umol),8-fluoro-2-methylbenzo[d][1,2,3]diazaborinine-1,7(2H)-diol (29.0 mg,149.5 umol, 1.0 eq) and K₂CO₃ (61.9 mg, 448.5 umol) in DMF (5 mL) wasstirred at 50° C. for 3 hours. Water was added to the mixture, andfiltered to give crude product, which was purified by pre-HPLC (column:Waters Xbridge 150×25 mm, 5 μm; liquid phase: [A-10 mM NH₄HCO₃ in H₂O;B-ACN] B %: 1%-25%, 12 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-2-methyl-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(36.0 mg, 43.4% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.93(d, J=2.4 Hz, 1H), 7.54-7.44 (m, 2H), 6.10 (dd, J=11.2, 17.6 Hz, 1H),5.60 (d, J=8.4 Hz, 1H), 5.10-4.98 (m, 2H), 4.94 (d, J=3.6 Hz, 1H), 3.49(s, 3H), 3.40 (d, J=6.4 Hz, 1H), 2.40 (brs, 1H), 2.24-1.97 (m, 5H),1.72-1.19 (m, 10H), 1.04 (s, 4H), 0.81 (d, J=7.2 Hz, 3H), 0.63 (d, J=7.2Hz, 3H). MS (ESI): mass calcd. for C₃₀H₄₀BFN₂O₆ 554.5, m/z found 555.3[M+H]⁺. HPLC: 100.00% (220 nm), 100.00% (254 nm).

86.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate (300.0 mg, 594.8 umol, 1.0 eq),1-(1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone (121.3 mg,594.8 umol, 1.0 eq) and K₂CO₃ (246.6 mg, 1.7 mmol, 3.0 eq) in DMF (10mL) was stirred at 50° C. for 1.5 hours. Water (30 mL) was added to themixture and acidified with 2N HCl (aq), white solid was precipitated andfiltered to give the crude product, which was purified by prep-HPLC(Instrument: Gilson 281 semi-preparative HPLC system. Column: DurashellC18 150×25 mm, 5 μm. Mobile phase: A: 5 mM NH₄HCO₃ in H₂O; B: ACNGradient: B % 15-100, 14.6 min. Flow rate: 25 ml/min. Monitorwavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (10.0 mg, 17.2 umol, 2.9% yield) as whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.03 (s, 1H), 7.52 (d, J=8.0 Hz, 1H),7.06-7.03 (m, 1H), 7.02-6.98 (m, 1H), 6.12-6.07 (m, 1H), 5.53 (d, J=5.6Hz, 1H), 5.11-4.97 (m, 2H), 4.83-4.75 (m, 2H), 4.63 (m, 1H), 3.75 (br.s., 1H), 2.39-2.31 (m, 4H), 2.14-1.66 (m, 4H), 1.44-1.26 (m, 8H),1.11-0.96 (m, 4H), 0.82 (d, J=6.6 Hz, 3H), 0.66-0.57 (m, 3H). MS (ESI):mass calcd. for C₃₁H₄₁BN₂O₈ 580.3, m/z found 596.9 (M+H₂O−H)⁻. HPLC:92.2% in 220 nm; 100% in 254 nm.

87.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

4-(benzyloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(200.0 mg, 591.0 umol) and acetylhydrazine (44.0 mg, 591.0 umol) inanhydrous ethanol (20 mL) were stirred at 60-70° C. overnight, whitesolid was precipitated. The mixture was filtered to give1-(7-(benzyloxy)-1-hydroxybenzo [d][1,2,3]diazaborinin-2(1H)-yl)ethanone(120.0 mg, 68.0%) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.03 (s,1H), 7.56 (d, J=8.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.38 (t, J=7.2 Hz, 2H),7.33 (d, J=7.0 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.10 (dd, J=2.8, 8.4 Hz,1H), 5.24-5.10 (m, 2H), 2.37 (s, 3H).

To a solution of 1-(7-(benzyloxy)-1-hydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone (300.0 mg, 1.0 mmol, 1.0 eq) inDCM (10 mL) was added trichloroborane (2 mL, 2.0 mmol, 2.0 eq) at 0° C.over a period of 30 min under N₂. During which the temperature wasmaintained below 0° C. The reaction mixture was warmed to 25° C. over aperiod of 30 mins and stirred at room temperature for 2 hours. Thesolvent was evaporated, water (50 mL) was added to the mixture and solidprecipitated, the mixture was filtered to give1-(1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone (200.0 mg,980.4 umol, 96.1% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ10.58-9.62 (m, 1H), 7.94 (s, 1H), 7.42 (d, J=8.2 Hz, 1H), 6.98 (d, J=2.2Hz, 1H), 6.83 (dd, J=2.2, 8.2 Hz, 1H), 2.34 (s, 3H).

Tos-pleuromutilin (400.0 mg, 750.0 umol),1-(1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone (153.0 mg,750.0 umol) and potassium carbonate (311.0 mg, 2.3 mmol) in DMF (5 mL)with cata. amount of potassium iodide were heated to 50° C. for 1 hour,HPLC showed the reaction was completely, water was added and acidifiedwith 2N HCl (aq), white solid was precipitated and filtered to givecrude product which was purified by prep-HPLC (Instrument: Gilson 281semi-preparative HPLC system. Column: Durashell C18 150×25 mm, 5 μm.Mobile phase: A: 5 mM NH₄HCO₃ in H₂O; B: ACN Gradient: B % 25-100, 14.6min. Flow rate: 25 ml/min. Monitor wavelength: 220&254 nm) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (75.0 mg, yield 17.0%) as white solid. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.07-6.94(m, 2H), 6.16-6.03 (m, 1H), 5.56 (t, J=8.0 Hz, 1H), 5.11-4.96 (m, 2H),4.77 (t, J=10.0 Hz, 2H), 4.53 (d, J=5.8 Hz, 1H), 3.39 (d, J=5.2 Hz, 1H),2.36 (d, J=1.4 Hz, 3H), 2.23-1.94 (m, 4H), 1.63 (br. s., 2H), 1.49-1.09(m, 7H), 1.00 (d, J=17.8 Hz, 4H), 0.80 (d, J=3.6 Hz, 3H), 0.61 (dd,J=7.0, 12.0 Hz, 3H). MS (ESI): mass calcd. for C₃₁H₄₁BN₂O₇ 564.3, m/zfound 581.3 (M+H₂O−H)⁻. HPLC: 94.9% in 220 nm; 100% in 254 nm.

88.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy) acetate (800.0 mg, 1.3 mmol, 1.0 eq),1-(1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone (282.0 mg,1.3 mmol, 1.0 eq) in DMF (20 mL) was added K₂CO₃ (572.2 mg, 4.1 mmol,3.0 eq) and the mixture was stirred at 50° C. for 2 hours. Water wasadded to the mixture and acidified with 2N HCl (aq), white solid wasprecipitated and filtered to give the crude product(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(700.0 mg, crude) as yellow solid.

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (700.0 mg, 1.2mmol, 1.0 eq) and K₂CO₃ (476.0 mg, 3.5 mmol) in MeOH (60 mL) was stirredat 50° C. for 2 hours. The mixture was filtered and evaporated to givethe crude product which was purified by prep-HPLC (Instrument: ShimadzuLC-20AP preparative HPLC system. Column: Phenomenex Luna (2) C18 250×50mm, 5 μm. Mobile phase: A: TFA/H₂O=0.075% v/v; B: ACN Gradient: B %15-45, 23 min. Flow rate: 80 ml/min. Monitor wavelength: 220&254 nm) andthen recrystallized from DCM/Petroleum ether (10:1) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate (22.0 mg, 33.6umol, 2.9% yield, 89.0% purity) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 8.02 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H),6.10-6.02 (m, 1H), 5.54 (s, 1H), 5.12-4.97 (m, 3H), 4.87-4.64 (m, 4H),3.30 (m, 1H), 2.36 (d, J=1.2 Hz, 3H), 2.25-1.96 (m, 4H), 1.43-1.22 (m,7H), 1.12-0.98 (m, 4H), 0.86-0.80 (m, 3H), 0.62 (m, 3H). MS (ESI): masscalcd. for C₃₁H₄₀BFN₂O₇ 582.3, m/z found 599.3 (M+H₂O−H)⁻. HPLC: 89.0%in 220 nm; 100% in 254 nm.

89.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-8-fluoro-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate

A solution of4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (500.0 mg, 1.4 mmol) and acetohydrazide (104.0 mg, 1.4mmol) EtOH (15 mL) was stirred at 50° C. for 12 hours. The mixture wasadded to product1-(7-(benzyloxy)-8-fluoro-1-hydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone(420.0 mg, crude) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.04 (d,J=2.2 Hz, 1H), 7.49-7.30 (m, 7H), 5.26 (d, J=3.2 Hz, 1H), 2.42 (s, 3H).

BCl₃ (1 M, 6.1 mL) was added to a solution of1-(7-(benzyloxy)-8-fluoro-1-hydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone(474.0 mg, 1.5 mmol) in DCM (25 mL) at 0° C., the mixture was stirred at0° C. for 2 hrs. The mixture was filtered to give1-(8-fluoro-1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone(300.0 mg, 88.9% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.97 (d, J=2.4 Hz,1H), 7.29 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.40 (s, 3H).

A solution of1-(8-fluoro-1,7-dihydroxybenzo[d][1,2,3]diazaborinin-2(1H)-yl)ethanone(50.0 mg, 225.3 umol), pleuromutilitosylate (120.0 mg, 225.3 umol) andK₂CO₃ (93.4 mg, 675.8 umol) in DMF (10 mL) was stirred at 50° C. for 2hours. Water was added to the mixture and filtered to give crudeproduct, which was purified by pre-HPLC (column: Waters Xbridge 150×25mm, 5 μm; liquid phase: [A-10 mM NH₄HCO₃ in H₂O; B-ACN] B %: 1%-25%, 12min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-acetyl-8-fluoro-1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-7-yl)oxy)acetate(25.0 mg, 15.6% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.05(s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.17-7.12 (m, 1H), 6.15-6.07 (m, 1H),5.61 (d, J=7.6 Hz, 1H), 5.13-5.00 (d, J=3.6 Hz, 2H), 4.97-4.83 (m, 2H),4.56-4.50 (m, 1H), 2.44-2.38 (m, 2H), 2.23-2.00 (m, 7H), 1.70-1.19 (m,11H), 1.05 (d, J=3.2 Hz, 3H), 0.82 (d, J=6.8 Hz, 3H), 0.65 (dd, J=6.8,17.6 Hz, 2H). MS (ESI): mass calcd. for C₃₁H₄₀BFN₂O₇ 582.5, m/z found583.3 (M+H)⁺. HPLC: 90.0% (220 nm), 90.4% (254 nm).

90. Methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

To a solution of (2-formyl-5-hydroxyphenyl)boronic acid (2.0 g, 12.1mmol, 1.0 eq) and methyl hydrazinecarbamate (1.1 g, 12.0 mmol) in EtOH(20 mL) was stirred at 50° C. for 12 hours. The mixture was filtered togive methyl 1,7-dihydroxybenzo[d][1,2,3] diazaborinine-2(1H)-carboxylate(1.2 g, 5.5 mmol, 45.3% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz)δ 10.32 (s, 1H), 8.48 (s, 1H), 8.04 (s, 1H), 7.67 (d, J=8.4 Hz, 1H),7.42 (d, J=2.4 Hz, 1H), 7.19 (dd, J=2.4, 8.4 Hz, 1H), 3.90 (s, 1H).

A solution(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-iodoacetate (300.0 mg, 594.8 umol, 1.0 eq), methyl1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (130.8 mg,594.8 umol, 1.00 eq) and K₂CO₃ (246.6 mg, 1.7 mmol, 3.0 eq) in DMF (15mL) was stirred at 50° C. for 1 hour. Water was added to the mixture andacidified with 2N HCl (aq), white solid was precipitated and filtered togive the crude product, which was purified by prep-HPLC (Instrument:Gilson 281 semi-preparative HPLC system. Column: Luna C18 100×30 mm, 5μm. Mobile phase: A: 5 mM NH₄HCO₃ in H₂O; B: ACN Gradient: B % 32-100,14.6 min. Flow rate: 25 ml/min. Monitor wavelength: 220&254 nm) to givemethyl 7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(21.0 mg, 35.2 umol, 5.9% yield) as white solid, ¹H NMR (DMSO-d₆, 400MHz) δ 8.41 (s, 1H), 8.10 (s, 1H), 7.75 (d, 1H), 7.47 (s, 1H), 7.37 (d,1H), 6.10 (dd, J=11.2, 17.8 Hz, 1H), 5.65-5.51 (m, 2H), 5.12-4.97 (m,2H), 4.90 (d, J=8.0 Hz, 1H), 4.66 (d, J=6.4 Hz, 1H), 3.90 (s, 3H), 3.76(m, 1H), 2.36 (s, 1H), 2.13-1.96 (m, 3H), 1.88-1.69 (m, 3H), 1.46-1.16(m, 8H), 1.04 (m, 3H), 0.82 (d, J=6.8 Hz, 3H), 0.68 (m, 3H). MS (ESI):mass calcd. for C₃₁H₄₁BN₂O₉ 596.3, m/z found 594.8 (M−H)⁻. HPLC: 93.8%in 220 nm; 94.0% in 254 nm.

91. Methyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

To a solution of Tos-pleuromutilin (400.0 mg, 750.9 umol, 1.0 eq) andmethyl 1,7-dihydroxybenzo[d][1,2,3] diazaborinine-2(1H)-carboxylate(165.2 mg, 750.9 umol, 1.0 eq) in DMF (15 mL) was added K₂CO₃ (310 mg,2.2 mmol, 3.0 eq) and the mixture was stirred at 50° C. for 2 hours.Water was added to the mixture and acidified with 2N HCl (aq), whitesolid was precipitated and filtered to give crude product which waspurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Luna C18 100×30 mm, 5 μm. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 45-100, 16 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give methyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate (126.0 mg, 34.4% yield) as white solid,¹H NMR (DMSO-d₆, 400 MHz) δ 8.12 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.48(s, 1H), 7.39 (dd, J=2.4, 8.4 Hz, 1H), 6.09 (dd, J=11.2, 17.6 Hz, 1H),5.60 (d, J=7.8 Hz, 1H), 5.13-4.97 (m, 2H), 4.96-4.84 (m, 2H), 3.91 (s,3H), 3.41 (d, J=5.8 Hz, 1H), 2.41 (s, 1H), 2.25-1.99 (m, 4H), 1.74-1.20(m, 10H), 1.10-0.94 (m, 4H), 0.81 (d, J=6.8 Hz, 3H), 0.67 (d, J=6.8 Hz,3H). MS (ESI): mass calcd. for C₃₁H₄₁BN₂O₈ 580.3, m/z found 597.4(M+H₂O−H)⁻. HPLC: 97.2% in 220 nm; 96.1% in 254 nm.

92. Methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

To a solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy) acetate (500.0 mg, 864.0 umol, 1.0 eq), methyl1,7-dihydroxybenzo[d][1,2,3] diazaborinine-2(1H)-carboxylate (190.0 mg,864.0 umol, 1.0 eq) in DMF (15 mL) was added K₂CO₃ (358.3 mg, 2.6 mmol,3.0 eq), the mixture was stirred at 50° C. for 2 hours. Water was addedto the mixture and acidified with 2N HCl (aq), white solid wasprecipitated and filtered to give the crude product methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(400.0 mg, crude) as yellow solid and used directly.

A solution of methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(500.0 mg, 798.1 umol, 1.0 eq) and K₂CO₃ (552.0 mg, 4.0 mmol, 5.0 eq) inMeOH (60 mL) was stirred at 50° C. for 5 hours. The mixture was filteredand the solvent was evaporated to give the crude product, which waspurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Synergi Max-RP C12 100×30 4 u. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 35-100, 16 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(38.0 mg, 63.5 umol, 7.9% yield) as yellow solid. ¹H NMR (DMSO-d₆, 400MHz) δ. 8.12 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.39 (d,J=8.8 Hz, 1H), 6.07 (dd, J=11.0, 18.0 Hz, 1H), 5.58-4.96 (m, 2H), 4.92(d, J=6.2 Hz, 2H), 3.91 (s, 3H), 3.34 (s, 1H), 2.61 (s, 1H), 2.27-1.93(m, 4H), 1.47-1.18 (m, 9H), 1.10-1.00 (m, 4H), 0.89-0.78 (m, 3H), 0.68(d, J=6.4 Hz, 3H). MS (ESI): mass calcd. for C₃₁H₄₀BFN₂O₈ 598.3, m/zfound 599.1 (M+H)⁺. HPLC: 91.1% in 220 nm; 93.5% in 254 nm.

93. Methyl8-fluoro-1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

To a solution of (2-fluoro-6-formyl-3-hydroxyphenyl)boronic acid (250.0mg, 1.4 mmol) and methyl N-aminocarbamate (122.2 mg, 1.4 mmol) in EtOH(5 mL) was stirred at 50° C. for 12 hours. The mixture was filtered togive the product methyl8-fluoro-1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(180.0 mg, 55.6% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ10.61 (s, 1H), 8.56 (brs, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 7.40-7.34 (m, 1H), 3.90 (s, 3H).

To a solution of methyl8-fluoro-1,7-dihydroxybenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(180.0 mg, 756.4 umol), pleuromutilitosylate (402.9 mg, 756.4 umol) andCs₂CO₃ (739.3 mg, 2.3 mmol) in DMF (5 mL) was stirred at 25° C. for 12hours. Water was added to the mixture and filtered to give the productmethyl 8-fluoro-1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)benzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(18.0 mg, 3.5% yield) as beige solid, which was purified by pre-HPLC(column: Waters Xbridge 150×25 mm, 5 μm; liquid phase: [A-10 mM NH₄HCO₃in H₂O; B-ACN] B %: 1%-25%, 12 min]). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.53(brs, 1H), 7.86 (brs, 1H), 7.48-7.29 (m, 2H), 6.11 (dd, J=10.8, 17.6 Hz,1H), 5.60 (d, J=8.0 Hz, 1H), 5.13-4.99 (m, 2H), 4.98-4.86 (m, 2H), 4.54(d, J=6.4 Hz, 1H), 3.84 (s, 2H), 3.44-3.39 (m, 1H), 2.41 (brs, 1H),2.29-2.00 (m, 3H), 1.73-1.19 (m, 10H), 1.11-0.94 (m, 4H), 0.81 (d, J=6.4Hz, 3H), 0.70-0.60 (m, 3H). MS (ESI): mass calcd. for C₃₁H₄₀BFN₂O 598.5,m/z found 599.3 (M+H)⁺. HPLC: 89.1% (220 nm), 100.0% (254 nm).

94. Methyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

To a solution of4-(benzyloxy)-3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(3.2 g, 9.1 mmol, 1.0 eq) in DCM (30 mL) was added BBr₃ (9.1 g, 36.3mmol, 4.0 eq). The mixture was stirred at 0° C. for 1 hour. HPLCindicated STM was consumed completely. The reaction mixture wasconcentrated, H₂O (20 mL) was added and then filtered to give a residue.The residue was washed by H₂O and DCM. The crude product(6-formyl-3-hydroxy-2-methylphenyl)boronic acid (1.5 g, 8.1 mmol, 88.7%yield) was used into the next step without further purification. ¹H NMR(DMSO-d₆, 400 MHz) δ 10.27 (s, 1H), 9.68 (s, 1H), 7.87 (s, 2H), 7.53 (d,J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 2.50 (s, 3H).

A solution of (6-formyl-3-hydroxy-2-methylphenyl)boronic acid (1.0 g,5.7 mmol, 1.0 eq) and methyl N-aminocarbamate (515.5 mg, 5.7 mmol, 1.0eq) in EtOH (10.0 mL) was stirred at 25° C. for 3 hours. HPLC indicatedSTM was consumed completely. The reaction mixture was concentrated toremove EtOH. The residue was diluted with MTBE (10 mL), the mixture wasfiltered to give a residue. The residue was washed by MTBE and PE (1:1)10 mL. methyl1,7-dihydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(1.1 g, 4.7 mmol, 82.2% yield) was obtained as a light gray solid. ¹HNMR (DMSO-d₆, 400 MHz) δ10.16 (s, 1H), 9.14 (s, 1H), 7.95 (s, 1H), 7.48(d, J=8.4 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 3.91 (s, 3H), 2.55 (s, 3H).MS (ESI): mass calcd. for C₁₀H₁₁BN₂O₄ 234.0, m/z found 235.1 [M+H]⁺.HPLC: 99.9% (220 nm), 100.0% (254 nm).

To a solution of methyl1,7-dihydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(100.0 mg, 427.3 umol, 1.0 eq) in DMF (10 mL) was added K₂CO₃ (177.2 mg,1.3 mmol, 3.0 eq) and KI (7.1 mg, 42.7 umol, 0.1 eq). The mixture wasstirred at 50° C. for 3 hours. HPLC indicated STM was consumedcompletely. The reaction mixture was quenched by addition H₂O (20 mL) at0° C., and then adjusted pH=7 with HCl (2M, 4 mL), filtered to give aresidue. The residue was dissolved by MTBE and PE, then concentrateduntil solid was dissolved out, filtered and concentrated the filtrateunder reduced pressure to give a residue, repeat four times. methyl1-hydroxy-7-(2-(((3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(35.0 mg, 54.7 umol, 12.8% yield, 93% purity) was obtained as a whitesolid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.15 (brs, 1H), 8.02 (brs, 1H), 7.59(brs, 1H), 7.33 (brs, 1H), 6.11 (dd, J=17.6, 11.2 Hz, 1H), 5.61 (d,J=8.4 Hz, 1H), 5.09-4.98 (m, 2H), 4.90 (s, 1H), 4.52 (d, J=2.4 Hz, 2H),3.90 (s, 3H), 3.41 (d, J=5.6 Hz, 1H), 2.33 (s, 3H), 2.20-2.05 (m, 4H),1.72-1.55 (m, 2H), 1.54-1.36 (m, 2H), 1.34 (s, 3H), 1.31-1.15 (m, 3H),1.03 (m, 4H), 0.82 (d, J=6.8 Hz, 3H), 0.65 (d, J=6.8 Hz, 3H). MS (ESI):mass calcd. for C₃₂H₄₃BN₂O₈, 594.5, m/z found 595.4 [M+H]⁺. HPLC: 93.0%(220 nm), 88.6% (254 nm).

95. Methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate

A mixture of methyl1,7-dihydroxy-8-methyl-2,3,1-benzodiazaborinine-2-carboxylate (150.0 mg,641.0 umol, 1.0 eq),(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy)acetate(370.9 mg, 641.0 umol, 1.0 eq) and Na₂CO₃ (135.9 mg, 1.28 mmol, 2.0 eq)in DMF (15.0 mL) was degassed and purged with N₂ for 3 times, and thenthe mixture was stirred at 50° C. for 3 hour under N₂ atmosphere. Thereaction mixture was quenched by addition H₂O 30 mL at 25° C., and thenadjusted pH<4 with 2N HCl aqueous solution and filtered to give crudemethyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-)oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(360.00 mg, crude) as white solid and used directly.

To a solution of methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(360.0 mg, 562.1 umol, 1.0 eq) in MeOH (50 mL) was added NaHCO₃ (236.1mg, 2.8 mmol, 5.0 eq). The mixture was stirred at 50° C. for 4 hours.The mixture was filtered and washed with MeOH 50 mL, the filtrate wasconcentrated in pressure to afford crude product. The crude product waspurified by Prep-HPLC. The solvent was concentrated until water left andfreeze-dried by lyophilizer to give methyl7-(2-(((2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl)oxy)-2-oxoethoxy)-1-hydroxy-8-methylbenzo[d][1,2,3]diazaborinine-2(1H)-carboxylate(40.0 mg, 65.3 umol, 11.6% yield) as white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 9.12 (s, 1H), 8.03 (s, 1H), 7.65-7.55 (m, 1H), 7.39-7.28 (m, 1H),6.09 (dd, J=11.2, 17.6 Hz, 1H), 5.59 (d, J=8.0 Hz, 1H), 5.14-4.83 (m,6H), 4.68 (d, J=6.4 Hz, 3H), 3.91 (s, 3H), 2.64 (s, 3H), 2.15-1.12 (m,10H), 1.03 (m, 4H), 0.83 (d, J=6.4 Hz, 3H), 0.66 (d, J=6.4 Hz, 3H). MS(ESI): mass calcd. for C₃₂H₄₂BFN₂O₈ 612.5, m/z found 629.4 (M+H₂O−H)⁻.HPLC: 100.0% (220 nm), 100.0% (254 nm).

96.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate

To a solution of (2-formyl-5-hydroxyphenyl)boronic acid (200.0 mg, 1.2mmol, 1.0 eq) in EtOH (20 mL) was stirred at 50° C. for 12 hours. Themixture was filtered to give 1H-benzo[d][1,2,6]oxazaborinine-1,7-diol(150.0 mg, 909.4 umol, 75.2% yield) as brown solid.

A solution of Tos-pleuromutilin (200.0 mg, 375.5 umol, 1.0 eq),1H-benzo[d][1,2,6]oxazaborinine-1,7-diol (61.1 mg, 375.5 umol, 1.00 eq)and K₂CO₃ (155.7 mg, 1.1 mmol, 3.0 eq) in DMF (15 mL) was stirred at 50°C. for 3 hours. Water was added to the mixture and acidified with 2N HCl(aq), white solid was precipitated and filtered, the crude productpurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Synergi Max-RP C12 100×30 4 u. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 35-100, 16 min. Flow rate: 20ml/min. Monitor wavelength: 220&254 nm) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate (10.0 mg,19.1 umol, 5.1% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.29(s, 1H), 8.54 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.49 (s, 1H), 7.37 (d,J=6.0 Hz, 1H), 6.13-6.04 (m, 1H), 5.60 (d, J=7.8 Hz, 1H), 5.11-4.96 (m,2H), 4.87 (d, J=7.2 Hz, 1H), 4.53 (d, J=6.2 Hz, 1H), 3.41 (m, 1H), 2.41(s, 1H), 2.05 (m, 4H), 1.71-1.44 (m, 4H), 1.40-1.20 (m, 7H), 1.04 (s,4H), 0.81 (d, J=6.8 Hz, 3H), 0.65 (d, J=7.0 Hz, 3H). MS (ESI): masscalcd. for C₂₉H₃₈BNO₇ 523.3, m/z found 522.3 (M−H)⁻. HPLC: 97.5% in 220nm; 94.3% in 254 nm.

97.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate

BCl₃ (1 M, 22.44 mL) was added to a solution of4-(benzyloxy)-3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(2.0 g, 5.6 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at 0°C. for 3 hours. Water (50 mL) was added to quench the reaction, themixture was extracted with EtOAc (50 mL) twice, the combined organiclayers were concentrated to give(2-fluoro-6-formyl-3-hydroxyphenyl)boronic acid (1.0 g, 82.4% yield) asgreen solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.82 (s, 1H), 9.74 (d, J=2.8Hz, 1H), 8.17 (s, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.4 Hz, 1H).

(2-fluoro-6-formyl-3-hydroxyphenyl)boronic acid (300.0 mg, 1.6 mmol),NH₂OH.HCl (124.6 mg, 1.8 mmol) and KOAc (191.9 mg, 1.9 mmol) in H₂O (5mL) and EtOH (5 mL) were stirred at 50° C. for 2 hours. The mixture wasfiltered to give 8-fluoro-1H-benzo[d][1,2,6]oxazaborinine-1,7-diol(190.0 mg, crude). ¹H NMR (DMSO-d₆, 400 MHz) δ 10.70 (s, 1H), 8.48 (d,J=2.8 Hz, 1H), 7.46-7.43 (m, 1H), 7.40-7.34 (m, 1H).

A solution of 8-fluoro-1H-benzo[d][1,2,6]oxazaborinine-1,7-diol (190.0mg, 1.1 mmol) and pleuromutilitosylate (559.4 mg, 1.1 mmol) and K₂CO₃(435.4 mg, 3.2 mmol) in DMF (5 mL) was stirred at 50° C. for 2 hours.Water was added to the mixture and filtered to give crude product, whichwas purified by pre-HPLC (column: Waters Xbridge 150×25 mm, 5 μm; liquidphase: [A-10 mM NH₄HCO₃ in H₂O; B-ACN] B %: 1%-25%, 12 min]) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((8-fluoro-1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate(6.0 mg, 1.00% yield) as beige solid. ¹H NMR (DMSO-d₆, 400 MHz) δ9.44-9.27 (m, 1H), 8.55 (brs, 1H), 7.54 (brs, 2H), 6.10 (dd, J=11.2,17.6 Hz, 1H), 5.59 (d, J=8.8 Hz, 1H), 5.23-4.90 (m, 4H), 4.54 (brs, 1H),2.40 (brs, 1H), 2.24-1.97 (m, 4H), 1.72-1.19 (m, 10H), 1.10-0.94 (m,3H), 0.81 (d, J=6.4 Hz, 3H), 0.64 (d, J=7.2 Hz, 3H). MS (ESI): masscalcd. for C₂₉H₃₇BFNO₇ 541.4, m/z found 558.3 (M+H₂O−H)⁻. HPLC: 94.9%(220 nm), 95.8% (254 nm).

98.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy) acetate (500.0 mg, 911.2 umol, 1.0 eq),1H-benzo[d][1,2,6]oxazaborinine-1,7-diol (148.4 mg, 911.2 umol, 1.0 eq)and K₂CO₃ (377.8 mg, 2.7 mmol, 3.0 eq) in DMF (15 mL) was stirred at 50°C. for 2 hours. Water was added to the mixture and acidified with 2N HCl(aq), white solid was precipitated and filtered to give the crudeproduct, which was purified by prep-HPLC (Instrument: Gilson 281semi-preparative HPLC system. Column: Synergi Max-RP C12 100×30 4 u.Mobile phase: A: TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 30-100, 16min. Flow rate: 25 ml/min. Monitor wavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2,8-dihydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6] oxazaborinin-7-yl)oxy)acetate (12.0 mg,22.3 umol, 2.4% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.51(s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.46 (d, J=2.8 Hz, 1H), 7.34 (dd,J=2.8, 8.4 Hz, 1H), 6.09 (dd, J=11.2, 17.6 Hz, 1H), 5.55 (d, J=8.4 Hz,1H), 5.09-5.01 (m, 2H), 4.85 (d, J=6.8 Hz, 1H), 4.52 (s, 2H), 3.75-3.71(m, 1H), 3.30 (d, J=5.6 Hz, 1H), 2.31 (s, 1H), 2.14-1.93 (m, 2H),1.87-1.69 (m, 2H), 1.45-1.16 (m, 8H), 1.09-0.97 (m, 4H), 0.81 (d, J=7.0Hz, 3H), 0.67-0.57 (m, 3H). MS (ESI): mass calcd. for C₂₉H₃₈BNO₈ 539.3,m/z found 540.3 (M+H)⁺. HPLC: 95.8% in 220 nm; 98.8% in 254 nm.

99.(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(tosyloxy) acetate (800.0 mg, 1.3 mmol, 1.0 eq),1H-benzo[d][1,2,6]oxazaborinine-1,7-diol (225.3 mg, 1.3 mmol, 1.0 eq)and K₂CO₃ (572.2 mg, 4.1 mmol, 3.0 eq) in DMF (25 mL) was stirred at 50°C. for 2 hours. Water was added to the mixture and acidified with 2N HCl(aq), white solid was precipitated and filtered to give the crudeproduct(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6] oxazaborinin-7-yl)oxy)acetate (620.0mg, crude) as yellow solid and used directly.

A solution of(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-(formyloxy)-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6] oxazaborinin-7-yl)oxy)acetate (620.0mg, 1.1 mmol, 1.0 eq) and K₂CO₃ (752.0 mg, 5.5 mmol, 5.0 eq) in MeOH(100 mL) was stirred at room temperature for 2 hours. The mixture wasfiltered and the solvent was evaporated to give crude product, which waspurified by prep-HPLC (Instrument: Gilson 281 semi-preparative HPLCsystem. Column: Synergi Max-RP C12 100×30 4 u. Mobile phase: A:TFA/H₂O=0.075% v/v; B: ACN Gradient: B % 40-100, 16 min. Flow rate: 25ml/min. Monitor wavelength: 220&254 nm) to give(2S,3aR,4R,5R,7S,8S,9R,9aS,12R)-2-fluoro-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1H-benzo[d][1,2,6]oxazaborinin-7-yl)oxy)acetate (18.0 mg,33.3 umol, 3.1% yield) as white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.54(s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (s, 1H), 7.38 (dd, J=2.4, 8.2 Hz,1H), 6.07 (dd, J=11.0, 17.6 Hz, 1H), 5.58 (d, J=7.8 Hz, 1H), 5.11-4.89(m, 5H), 2.61 (s, 1H), 2.25-1.96 (m, 4H), 1.81 (d, J=14.0 Hz, 1H),1.46-1.19 (m, 9H), 1.10-0.96 (m, 4H), 0.84 (d, J=7.0 Hz, 3H), 0.66 (d,J=6.6 Hz, 3H). MS (ESI): mass calcd. for C₂₉H₃₇BFNO₇ 541.3, m/z found540.0 (M−H). HPLC: 92.0% in 220 nm; 94.0% in 254 nm.

100.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-c]pyridin-6-yl)oxy)acetate

To a solution of benzyl alcohol (8.20 mL, 79.4 mmol) in DMF (100 mL)cooled in ice-water bath was added NaH (3.46 g, 86.6 mmol) in portions.The reaction was stirred for 30 min at 0° C. Then6-chloronicotinonitrile (10.00 g, 72.2 mmol) was added. The mixture wasstirred for 30 min at room temperature. Then the reaction was quenchedby ice water (200 mL), white solid precipitated. The mixture wasfiltered and the cake was washed with cold water, dried to give6-(benzyloxy)nicotinonitrile (15.9 g, yield 100%) as white solid. ¹H NMR(MeOD, 400 MHz) δ 8.55 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.44-7.31 (m,5H), 6.96 (d, J=8.0 Hz, 1H), 5.45 (s, 2H).

To a solution of 6-(benzyloxy)nicotinonitrile (14.8 g, 70.5 mmol) inanhydrous THF (700 mL) was added LDA (42 mL, 82 mmol) dropwise at −78°C. The reaction mixture was stirred at −78° C. for 30 min. Thentriisopropyl borate (32.3 mL, 140 mmol) was added to the mixturedropwise. The reaction was gradually warmed to room temperature andstirred for 30 min at this temperature. The reaction was quenched byadding water (300 mL) and extracted with MTBE (200 mL) twice. Then thepH of the aqueous layer was adjusted to 6˜7 and extracted with EtOAc(300 mL) three times. The combined EtOAc layers were washed with brine,dried over Na₂SO₄ and concentrated. The residue was recrystallized bypetroleum ether and EtOAc (˜10:1) to give the desired product(2-(benzyloxy)-5-cyanopyridin-4-yl)boronic acid (11.2 g, yield 63%) aslight yellow solid. ¹H NMR (MeOD, 400 MHz) δ 8.46 (s, 1H), 7.44-7.30 (m,5H), 7.08 (s, 1H), 5.41 (s, 2H).

A solution of (2-(benzyloxy)-5-cyanopyridin-4-yl)boronic acid (11.2 g,44 mmol) in hydrochloride gas/methanol solution (100 mL, 4 mol/L) wasstirred at 0° C. for 1 h. Then the solvent was evaporated and theresidue was recrystallized by petroleum ether and EtOAc (10:1) to give(2-(benzyloxy)-5-(methoxycarbonyl)pyridin-4-yl)boronic acid (8.9 g,yield 70.6%) as milky solid. ¹H NMR (MeOD, 400 MHz) δ 8.77 (s, 3H),7.45-7.30 (m, 5H), 6.82 (s., 1H), 5.43 (s, 2H), 3.92 (s, 3H).

A solution of (2-(benzyloxy)-5-(methoxycarbonyl)pyridin-4-yl)boronicacid (1.0 g, 3.5 mmol) in MeOH (30 mL) was cooled with ice-water bath,to this solution was added NaBH₄ (1.3 g, 34.8 mmol) in portions. Thereaction was quenched by adding of 3N aq.HCl solution (˜10 mL). Themixture was then concentrated and the residue was partitioned betweenEtOAc and water. The pH the hydrous layer was adjusted to 6˜7 andextracted with EtOAc for three times. The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by prep-HPLC to give the desired product6-(benzyloxy)-[1,2]oxaborolo[4,3-c]pyridin-1(3H)-ol (630 mg, yield75.1%) as yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.28 (s, 1H),7.45-7.31 (m, 5H), 7.12 (s, 1H), 5.37 (s, 2H), 5.02 (s, 2H) MS (ESI):mass calcd. for C₁₃H₁₂BNO₃ 241.1, m/z found 242.1 [M+1]⁺. HPLC: 99.5%(220 nm), 99.2% (254 nm).

A suspension of 6-(benzyloxy)-[1,2]oxaborolo[4,3-c]pyridin-1(3H)-ol (300mg, 1.2 mmol) and Pd/C (80 mg) in EtOAc (40 mL) was hydrogenated under50 Psi of hydrogen pressure overnight at room temperature. The mixturewas filtered through a pad of silica gel and the pad was washed withMeOH (20 mL). The combined filtrate was concentrated to dryness. Thecrude product was recrystallized with EtOAc to afford[1,2]oxaborolo[4,3-c]pyridine-1,6(3H)-diol (160 mg, yield 85%) as lightbrown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.69 (s, 1H), 6.94 (s, 1H),4.89 (s, 2H). MS (ESI): mass calcd. for C₆H₆BNO₃ 151.0, m/z found 152.1[M+1]⁺. HPLC: 95.0% (220 nm).

To a solution of [1,2]oxaborolo[4,3-c]pyridine-1,6(3H)-diol (60 mg, 0.4mmol), Cs₂CO₃ (391 mg, 1.2 mmol) and a trace amount catalytic of waterin DMF (10 mL) was added Iodo-pleuromutilin (200 mg, 0.4 mmol), thereaction mixture was bubbled with N₂ for 5 mins then sealed and heatedin microwave at 60° C. for 45 min. The reaction was quenched by additionof water (20 mL). The pH of mixture was adjusted to 6˜7 and extractedwith EtOAc for three times. The combined organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-c]pyridin-6-yl)oxy)acetate(41 mg, yield 19.6%) as off white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.70 (s, 1H), 6.71 (s, 1H), 6.12 (dd, J_(1,2)=10.8 Hz, J_(1,3)=17.6 Hz,1H), 5.51 (d, J=8.0 Hz, 1H), 5.14 (d, J=16.0 Hz, 1H), 5.02 (d, J=12.0Hz, 1H), 4.88 (s, 2H), 4.61 (d, J=5.2 Hz, 2H), 3.42 (d, J=4.0 Hz, 1H),2.39 (s, 1H), 2.17-2.00 (m, 4H), 1.67-1.60 (m, 2H), 1.47-1.26 (m, 9H),1.06-0.95 (m, 4H), 0.81 (d, J=8.0 Hz, 3H), 0.66 (d, J=8.0 Hz, 3H). MS(ESI): mass calcd. for C₂₈H₃₈BNO₇ 511.3, m/z found 528.2 [M+H₂O−1]⁻.HPLC: 99.4% (220 nm), 100% (254 nm).

101.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-b]pyridin-6-yl)oxy)acetate

To a solution of benzyl alcohol (4.3 mL, 42.8 mmol) in DMF (100 mL)cooled in ice-water bath was added NaH (1.8 g, 45.6 mmol) in portions.The reaction was stirred for 1 h at 0° C. Then3,5-dibromopicolinonitrile (10.0 g, 38.0 mmol) was added. The mixturewas stirred for 30 min at room temperature. Then the reaction wasquenched by ice water and extracted with EtOAc for three times. Thecombined organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography to givea mixture of 5-(benzyloxy)-3-bromopicolinonitrile and3-(benzyloxy)-5-bromopicolinonitrile (5.13 g, yield 100%, ˜1:1 in ¹HNMR) as white solid. ¹H NMR (CD₃OD, 400 MHz) δ 8.55 (d, J=2.0 Hz, 1H),7.96-7.95 (m, 1H), 7.45-7.31 (m, 5H), 6.96 (d, J=8.8 Hz, 1H), 5.45 (s,2H).

To a mixture of 5-(benzyloxy)-3-bromopicolinonitrile and3-(benzyloxy)-5-bromopicolinonitrile (14.8 g, 17.3 mol) in water (100mL) was added NaOH (3.5 g, 86.5 mmol) and the mixture was heated toreflux overnight. The pH of the reaction mixture was adjusted to 5˜6 andextracted with EtOAc for three times. The combined organic layer waswashed with brine, dried over Na₂SO₄ and concentrated to give a mixtureof 5-(benzyloxy)-3-bromopicolinic acid and3-(benzyloxy)-5-bromopicolinic acid (7.0 g, yield 100%, ˜1:1 ratio).

A solution of 5-(benzyloxy)-3-bromopicolinic acid and3-(benzyloxy)-5-bromopicolinic acid (7.00 g, 23 mmol) in HCl gas/MeOH(100 mL, 4 mol/L) was heated to reflux overnight. Then the solvent wasevaporated and the residue was dissolved in water. The pH of the mixturewas adjusted to 7˜8 by adding aqueous NaHCO₃ solution, the resultingmixture was extracted with EtOAc for three times. The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography give methyl5-(benzyloxy)-3-bromopicolinate (2.0 g, yield 27.4%) as white solid. ¹HNMR (CD₃OD, 400 MHz) δ 8.32 (d, J=2.4 Hz, 1H), 7.81 (d, J=2.4 Hz, 1H),7.47-7.37 (m, 5H), 5.24 (s, 3H).

To a solution of methyl 5-(benzyloxy)-3-bromopicolinate (1.3 g, 4.0mmol) in anhydrous THF (700 mL) was added DIBAL-H (20 mL, 20 mmol)dropwise at −78° C. The reaction mixture was stirred at room temperaturefor 2 hs then quenched by slowly adding water (10 mL). The resultingmixture was dried over Na₂SO₄ and concentrated to give(5-(benzyloxy)-3-bromopyridin-2-yl)methanol (1.1 g, yield 93.2%) asyellow oil. ¹H NMR (CD₃OD, 400 MHz) δ 8.28 (d, J=2.8 Hz, 1H), 7.70 (d,J=2.8 Hz, 1H), 7.46-7.33 (m, 5H), 5.18 (s, 2H), 4.71 (s, 2H).

A suspension of (5-(benzyloxy)-3-bromopyridin-2-yl)methanol (1.8 g, 6.1mmol) and DIEA (2.4 g, 18.3 mmol) in DCM (40 mL) cooled in ice-waterbath was added MOMCl (1.0 g, 12.3 mmol) dropwise. The reaction wasstirred at room temperature overnight. The reaction was quenched bywater and extracted with DCM for three times. The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by column chromatography give the desired product (1.1 g,yield 53.4%).

A suspension of (5-(benzyloxy)-3-bromopyridin-2-yl)methanol (1.10 g, 3.3mmol) in dioxane (100 ml) was bubbled with N₂ for 20 min. Thenbis(pinacolato)dibarane (4.2 g, 16.5 mmol), PdCl₂(dppf)CH₂Cl₂ (0.2 g,0.3 mmol), KOAc (0.7 g, 6.6 mmol) was added under N₂ protection. And theresulting solution was warmed at 70° C. overnight. The reaction mixturewas then cooled and filtered through a celite pad. The filtrate wasconcentrated to provide the crude product(5-(benzyloxy)-2-((methoxymethoxy)methyl)pyridin-3-yl)boronic acid (6g).

To a solution of(5-(benzyloxy)-2-((methoxymethoxy)methyl)pyridin-3-yl)boronic acid (6.0g, crude) in THF (50 mL) was added hydrochloride acid (35 mL, 4 mol/L)and the mixture was stirred at 40° C. overnight. After cooled to roomtemperature, the mixture was poured into 50 mL of cold water andextracted with EtOAc (100 mL) three times, the combined organic layerswere concentrated and residue was purified by prep-HPLC (column: LunaC18 100×30 mm, 5 m; liquid phase: [A-TFA/H₂O=0.075% v/v; B-ACN] B %:20%-55%, 25 min]) to give6-(benzyloxy)-[1,2]oxaborolo[4,3-b]pyridin-1(3H)-ol (410 mg, yield19.6%) as off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.41 (s, 1H),7.67 (s, 1H), 7.48-7.36 (m, 5H), 5.21 (s, 2H), 4.89 (s, 2H).

A suspension of 6-(benzyloxy)-[1,2]oxaborolo[4,3-b]pyridin-1(3H)-ol (200mg, 0.83 mmol) and Pd/C (200 mg) in EtOAc/i-PrOH (50 mL, 1:1) wasstirred at 25° C. overnight under hydrogen atmosphere (50 Psi). Themixture was filtered and washed with MeOH. The filtrate wasconcentrated. The crude product was washed with MeCN and Petroleum etherto give [1,2]oxaborolo[4,3-b]pyridine-1,6(3H)-diol (120 mg, yield 96%).¹H NMR (DMSO-d₆, 400 MHz) δ 8.41 (s, 1H), 7.44 (s, 1H), 4.81 (s, 1H)

To a solution of [1,2]oxaborolo[4,3-b]pyridine-1,6(3H)-diol (50 mg, 0.33mmol), Iodo-pleuromutilin (161 mg, 0.33 mmol), and Cs₂CO₃ (324 mg, 0.99mol/L) in THF/H₂O (3 mL, 2:1) was sealed and heated under microwave at60° C. for 45 min under N₂ protection. The mixture was adjusted pH to5˜6 and the solvent was evaporated. The residue was purified by prep-TLC(n-BuOH: AcOH:water=7:1:2) to give(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-b]pyridin-6-yl)oxy)acetate(14 mg, yield 8.3%) as light yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.71-7.68 (m, 1H), 7.43-7.34 (m, 1H), 6.31-6.23 (m, 1H), 5.80 (d, J=7.6Hz, 1H), 5.19-5.07 (m, 4H), 3.48 (d, J=4.4 Hz, 1H), 2.37-1.13 (m, 21H),0.92 (d, J=6.4 Hz, 3H), 0.74 (d, J=6.4 Hz, 3H). MS (ESI): mass calcd.for C₂₈H₃₈BNO₇ 511.3, m/z found 528.2 [M+H₂O−1]⁻. HPLC: 92.5% (220 nm),92.4% (254 nm).

102.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-b]pyridin-6-yl)glycinate

To a suspension of NaH (60% in mineral oil, 3.0 g, 75.6 mmol) in DMF(100 mL) at 0° C. was slowly added ethyl malonate (12 mL, 75.6 mmol)over 20 min. The mixture was allowed to stir for 20 min at roomtemperature, during which time the suspension became a solution. Asolution of 3-bromo-2-chloro-5-nitropyridine (12.0 g, 50.4 mmol) in DMF(20 mL) was added slowly at 0° C. The resulting dark red mixture wasallowed to stir at 40° C. for 2 h. The reaction mixture was then pouredinto 200 mL water and extracted with ethyl acetate (3×80 mL). Theorganic solutions were combined, washed with water and brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel column chromatography using petroleum ether:ethylacetate:Et₃N=10:1:0.1 as eluent to give diethyl2-(3-bromo-5-nitropyridin-2-yl)malonate (17.3 g, yield 95%) as acolorless oil. MS (ESI): mass calcd. for C₁₂H₁₃BrN₂O₆ 360.00, m/z found361.0 [M+H]⁺.

Diethyl 2-(3-bromo-5-nitropyridin-2-yl) malonate (17.3 g, 48.1 mmol) wasrefluxed in 150 mL 6M HCl for 5 h. The reaction mixture then cooled toroom temperature and neutralized with NaOH in an ice bath to pH 10. Themixture was extracted with ethyl acetate (150 mL×2). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel by elution with petroleum ether:ethylacetate:Et₃N=10:1:0.1 to give 3-bromo-2-methyl-5-nitropyridine (8.37 g,yield 81%) as a white solid. MS (ESI): mass calcd. for C₆H₅BrN₂O₂215.95, m/z found 217.1 [M+H]⁺.

To a solution of 3-bromo-2-methyl-5-nitropyridine (2.0 g, 9.26 mmol) andNBS (2.0 g, 11.24 mmol) in CCl₄ (35 mL) was added BPO (448 mg, 1.85mmol). The reaction mixture was heated to reflux overnight. 100 mL waterwas added and extracted with DCM (30 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give 2.5 g of crude product3-bromo-2-(bromomethyl)-5-nitropyridine. It was used in next stepwithout further purification.

To a solution of crude 3-bromo-2-(bromomethyl)-5-nitropyridine (2.5 g,8.4 mmol) in DMF (30 mL) was added NaOAc (1.48 g, 18.0 mmol). Thereaction mixture was reacted at room temperature for 2 h, then ethylacetate (150 mL) was added. The mixture was washed with water (50 mL×3).The solvent was removed and the residue was purified by silica gelcolumn chromatography using petroleum ether: ethyl acetate=10:1 to give(3-bromo-5-nitropyridin-2-yl)methyl acetate (825 mg, yield 31% over twosteps) as a white solid. MS (ESI): mass calcd. for C₈H₇BrN₂O₄ 273.96,m/z found 275.0 [M+H]⁺.

To a solution of (3-bromo-5-nitropyridin-2-yl) methyl acetate (620 mg,2.26 mmol), Pin₂B₂ (1.15 g, 4.52 mmol) and KOAc (665 mg, 6.78 mmol) in1,4-dioxane (5 mL) was added PdCl₂(dppf)₂ (83 mg, 0.11 mmol). Thereaction mixture was stirred at 80° C. under argon atmosphere overnight.The solvent was removed and the residue was used in next step withoutfurther purification.

A mixture of(5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylacetate (about 290 mg, 0.9 mmol), NaOH (700 mg, 17.5 mmol) in H₂O (1.5mL) and THF (12 mL) was stirred at r.t for 4 h. Then the mixture wasadded HCl (6N) to pH=3 and continued to stir overnight. Water (10 mL)was added and the mixture was extracted with ethyl acetate (10 mL×2).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under the reduced pressure. The residue was purified byprep-HPLC to give 6-nitro-[1,2]oxaborolo[4,3-b]pyridin-1(3H)-ol (110 mg,yield 27% over two steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.83 (s, 1H), 9.44 (d, 1H), 8.82 (d, 1H), 5.12 (s, 2H). MS (ESI): masscalcd. for C₆H₅BN₂O₄ 180.03, m/z found 181.3 [M+H]⁺.

A mixture of 6-nitro-[1,2]oxaborolo[4,3-b]pyridin-1(3H)-ol (50 mg, 0.27mmol) and Pd/C (6 mg) in MeOH (6 mL) was stirred overnight at r.t underH₂ atmosphere. All insolubles were removed via filtration on Celite. Thesolvent was removed and the residue was used in next step withoutfurther purification. MS (ESI): mass calcd. for C₆H₇BN₂O₂ 150.06, m/zfound 151.3 [M+H]⁺.

A solution of crude 6-amino-[1,2]oxaborolo[4,3-b]pyridin-1(3H)-ol (40mg, 0.26 mmol) and I-Pleu (145 mg, 0.32 mmol) in DMF (2 mL) was stirredat 80° C. under argon atmosphere overnight. The mixture was purified byprep-HPLC under acid condition to(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl(1-hydroxy-1,3-dihydro-[1,2]oxaborolo[4,3-b]pyridin-6-yl)glycinate TFAsalt, 22 mg, yield 13% over two steps) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 6.72 (s, 2H),6.10 (q, 1H), 5.59-5.45 (m, 2H), 5.17-4.97 (m, 4H), 4.63 (d, 1H),3.44-3.38 (m, 2H), 2.45 (s, 1H), 2.19-1.99 (m, 4H), 1.67-1.26 (m, 10H),1.10-0.91 (m, 4H), 0.81 (d, 3H), 0.61 (d, 3H). HPLC purity: 100% (220nm), 100% (254 nm); MS (ESI): mass calcd. for C₂₈H₃₉BN₂O₆ 510.29, m/zfound 511.2 [M+H]⁺.

103.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(4-(2-hydroxy-2,5-dihydro-1,2-oxaborol-3-yl)phenoxy)acetate

To a solution of 4-iodophenol (20.0 g, 90.9 mmol, 1.00 eq) and DIEA(41.1 g, 318.2 mmol, 3.5 eq) in DCM (200 mL) was added MOMCl (14.6 g,181.80 mmol, 2.0 eq) drop-wise at 0° C. under N₂. The reaction mixturewas warmed to 25° C. stirred for 1 hour. TLC (Petroleum ether/Ethylacetate=3:1) showed the starting material was consumed completely. Thereaction was quenched by ice slowly and then extracted with DCM (100mL×2). The combined organic phase was washed with saturated brine (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo togive 1-iodo-4-(methoxymethoxy) benzene (18.0 g, 68.2 mmol, 75.0% yield)as light yellow oil. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.55-7.60 (m, 2H),6.80-6.85 (m, 2H), 5.15 (s, 2H), 3.47 (s, 3H).

1-iodo-4-(methoxymethoxy)benzene (17.0 g, 64.3 mmol, 1.0 eq),prop-2-yn-1-ol (7.2 g, 128.8 mmol, 2.0 eq), TEA (16.3 g, 161.0 mmol, 2.5eq), CuI (2.5 g, 12.9 mmol, 0.2 eq) and Pd(PPh₃)₂Cl₂ (2.3 g, 3.2 mmol,0.05 eq) in THF (200 mL) was degassed and then heated to 50° C. for 1hour under N₂. TLC (Petroleum ether/Ethyl acetate=3:1) showed thestarting material was consumed completely. The reaction mixture wasconcentrated in vacuum to give a residue, which was pre-purified bycolumn chromatography (Petroleum ether:EtOAc=5:1) to afford the pure3-[4-(methoxymethoxy)phenyl]prop-2-yn-1-ol (10.0 g, 52.0 mmol, 80.8%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.41 (m, 2H),6.96-6.01 (m, 2H), 5.19 (s, 2H), 4.49 (s, 2H), 3.48 (s, 3H).

To a solution of LiAlH₄ (1.2 g, 31.2 mmol, 1.2 eq) and NaOMe (3.1 g,57.2 mmol, 2.2 eq) in THF (100 mL) was added a solution of3-[4-(methoxymethoxy)phenyl]prop-2-yn-1-ol (5.0 g, 26.0 mmol, 1.0 eq) inTHF (25 mL) drop-wise at 0° C. The reaction mixture was stirred at 0° C.for 3 hours. Then 12 (13.2 g, 52.0 mmol, 2.0 eq) in THF (25 mL) wasadded dropwise and the mixture was stirred at 25° C. for 12 hours. TLC(Petroleum ether/Ethyl acetate=3:1) showed the starting material wasconsumed completely. The reaction was quenched by ice slowly and thenextracted with EtOAc (50 mL×2). The combined organic phase was washedwith saturated brine (50 mL) and saturated sodium thiosulfate solution(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=5/1) to give(Z)-3-iodo-3-[4-(methoxymethoxy)phenyl]prop-2-en-1-ol (5.0 g, 15.6 mmol,60.1% yield) as light yellow oil. ¹H NMR (DMSO-d₆, 400 MHz) δ 7.39-7.46(m, 2H), 6.95-7.02 (m, 2H), 6.17 (t, J=5.6 Hz, 1H), 5.19 (s, 2H), 4.38(d, J=5.6 Hz, 2H), 3.49 (s, 3H).

(Z)-3-iodo-3-[4-(methoxymethoxy)phenyl]prop-2-en-1-ol (2.0 g, 6.3 mmol,1.0 eq), BPD (3.2 g, 12.5 mmol, 2.0 eq), KOAc (1.8 g, 18.7 mmol, 3.0 eq)and Pd(dppf)Cl₂.CH₂Cl₂ (255.1 mg, 312.4 umol, 0.05 eq) in dioxane (40mL) was degassed and then heated to 100° C. for 12 hours under N₂. TLC(Petroleum ether/Ethyl acetate=3:1) showed the starting material wasconsumed completely. The reaction mixture was filtered, the filtrate wasconcentrated in vacuum to give a residue, which was purified bychromatography to afford2-hydroxy-3-[4-(methoxymethoxy)phenyl]-5H-oxaborole (310.0 mg, 1.4 mmol,22.5% yield) as light yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ7.56-7.62 (m, 2H), 7.40 (s, 1H) 6.93-6.99 (m, 2H), 5.17 (s, 2H), 4.64(d, J=1.6 Hz, 2H), 3.45 (s, 3H).

A mixture of 2-hydroxy-3-[4-(methoxymethoxy)phenyl]-5H-oxaborole (400.0mg, 1.8 mmol, 1.0 eq) and HCl (4 M, 10.0 mL) in THF (10 mL) was stirredat 20° C. for 2 hours. The reaction mixture extracted with EtOAc (10mL×2), washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give4-(2-hydroxy-5H-oxaborol-3-yl)phenol (280.0 mg, 1.6 mmol, 87.4% yield)as white solid. ¹H NMR (CD₃OD, 400 MHz) δ 7.50 (d, J=8.4 Hz, 2H), 7.32(s, 1H), 6.71 (d, J=8.8 Hz, 2H), 4.62 (s, 2H).

To a mixture of 4-(2-hydroxy-5H-oxaborol-3-yl)phenol (280.0 mg, 1.6mmol, 1.0 eq) and[(19R,20R,21R,22S,23R,26S,27R,28S)-22-hydroxy-19,20,26,27-tetramethyl-24-oxo-26-vinyl-21-tricyclotetradecanyl]2-(p-tolylsulfonyloxy)acetate (847.6 mg, 1.6 mmol, 1.0 eq) in DMF (10mL), was added Cs₂CO₃ (1.0 g, 3.2 mmol, 2.0 eq) in one portion under N₂.The mixture was stirred at 25° C. for 16 hours. HPLC shown main peak asdesired. Water (15 mL) was added and the mixture has a solidprecipitation. The solid was collected, then purified by prep-HPLC(column: Luna 300×50.0 mm, 10 μm; liquid phase: [A-H₂O+0.075% TFA;B-ACN] B %: 40%-70%, 20 min]) to afford(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-(4-(2-hydroxy-2,5-dihydro-1,2-oxaborol-3-yl)phenoxy)acetate(260.0 mg, 484.7 umol, 30.5% yield) as white solid. ¹H NMR (CD₃CN, 400MHz) δ 7.57 (d, J=6.8 Hz, 2H), 7.40 (s, 1H), 6.85 (d, J=7.0 Hz, 2H),6.27 (dd, J=17.6, 11.2 Hz, 2H), 5.73 (d, J=8.4 Hz, 1H), 5.15 (s, 1H),5.11 (m, 1H), 4.60 (s, 2H), 4.57 (s, 2H), 3.45 (d, J=7.0 Hz, 1H),2.32-1.45 (m, 12H), 1.38 (s, 3H), 1.08 (s, 3H), 0.86 (d, J=7.2 Hz, 3H),0.70 (d, J=7.2 Hz, 3H). MS (ESI): mass calcd. for C₃₁H₄₁BO₇ 536.3, m/zfound 535.3 [M−H]⁻. HPLC: 100% (220 nm), 100% (254 nm).

104.(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-methyl-1,2-dihydrobenzo[e][1,2]azaborinin-7-yl)oxy)acetate

To a suspension of potassium vinyltrifluoroborate (1.24 g, 7.39 mmol,1.1 equiv.), K₃PO₄ (4.27 g, 20.1 mmol, 3.0 equiv.), and Pd/C (10% w/w,140 mg) in NMP (6.7 mL) was added 5-bromo-2-iodo-aniline (2.0 g, 6.7mmol, 1.0 equiv.). The mixture was degassed with a stream of nitrogengas for 5 min, sealed with a Teflon lined cap and stirred at 100° C. for20 hours. HPLC indicated the reaction was completed. The reactionmixture was diluted with DCM (20 mL), filtered through a pad of Celiteand the eluent concentrated under reduced pressure to give the crudeproduct as a brown oil. The residue was purified by flash columnchromatography (100% DCM) to give 5-bromo-2-vinyl-aniline (2) (1.10 g,5.55 mmol, 83% yield) as a pale yellow oil. 1H NMR (CDCl₃, 400 MHz) δ7.12 (d, J=8.0 Hz, 1H), 6.88 (dd, J=1.6, 8.0 Hz, 1H), 6.85 (d, J=2.0,1H), 6.67 (dd, J=11.2, 17.6 Hz, 1H), 5.63 (dd, J=1.2, 17.2 Hz, 1H), 5.35(dd, J=1.2, 11.2 Hz, 1H), 4.10 (s, 2H).

To a microwave vial was added a stir bar, potassiumtrifluoromethylborate (128 mg, 1.05 mmol, 1.0 equiv.), and5-bromo-2-vinyl-aniline (250 mg, 1.26 mmol, 1.2 equiv.). The vial wassealed with a Teflon lined crimp cap, and purged and back-filled withnitrogen gas three times. Toluene (1 mL) and CPME (1 mL) were addedfollowed by SiCl₄ (121 uL, 1.05 mmol, 1.0 equiv.) with stirring. After 3minutes, TEA (215 uL, 1.58 mmol, 1.5 equiv.) was added and the reactionmixture was stirred at 45° C. for 20 hours. The reaction mixture wasdiluted with hexanes (5 mL) and purified by flash column chromatography(100% DCM) to give 7-bromo-2,1-borazaronaphthalene (3) (204 mg, 0.92mmol, 87% yield) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.85 (d,J=11.6 Hz, 1H), 7.55 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.35 (d, J=1.6,1H), 7.22 (dd, J=2.0, 8.4 Hz, 1H), 6.80 (dd, J=2.0, 11.6 Hz, 1H).

To a screw-cap vial was added 7-bromo-2,1-borazaronaphthalene (10 mg,0.045 mmol, 1.0 equiv.),(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-hydroxyacetate (51 mg, 0.13 mmol, 3.0 equiv.), NaOtBu (6 mg, 0.063mmol, 1.4 equiv.), tBuBrettPhos (1.1 mg, 0.002 mmol, 0.05 equiv.) andtBuBrettPhos palladium G3 precatalyst (1.9 mg, 0.002 mmol, 0.05 equiv.).The vial was sealed and purged and back-filled with nitrogen gas threetimes. Subsequently, 1,4-dioxane (0.10 mL) was added and the mixture wasstirred at 80° C. for 16 hours. The reaction mixture was quenched byaddition of MeOH (0.5 mL), and purified by prep-HPLC (column: Phenomenexluna C18 250×50 mm x 10 μm; liquid phase: [A-TFA/H₂O=0.1% v/v; B-ACN] B%: 50%-95%, 25 min]). The combined fractions were concentrated underreduced pressure to give the product(3aR,4R,5R,7S,8S,9R,9aS,12R)-8-hydroxy-4,7,9,12-tetramethyl-3-oxo-7-vinyldecahydro-4,9a-propanocyclopenta[8]annulen-5-yl2-((2-methyl-1,2-dihydrobenzo[e][1,2]azaborinin-7-yl)oxy)acetate (1.6mg, 0.003 mmol, 7% yield) as a light yellow solid. 1H NMR (CDCl₃, 400MHz) δ 7.84 (d, J=11.2 Hz, 1H), 7.51 (br s, 1H), 7.47 (d, J=8.8 Hz, 1H),6.74 (dd, J=2.4, 8.8 Hz, 1H), 6.65 (dd, J=1.2, 11.2 Hz, 1H), 6.61 (d,J=2.4 Hz, 1H), 6.53 (dd, J=11.2, 17.6 Hz, 1H), 5.88 (d, J=8.0 Hz, 1H),5.38 (dd, J=1.2, 11.2 Hz, 1H), 5.23 (dd, J=1.6, 17.6 Hz, 1H), 4.59 (s,2H), 3.38 (d, J=6.8 Hz, 1H), 2.40-2.30 (m, 1H), 2.30-2.00 (m, 5H),1.80-1.72 (m, 1H), 1.70-1.35 (m, 10H), 1.27-1.13 (m, 4H), 1.11 (s, 3H),0.89 (d, J=6.8 Hz, 3H), 0.71 (s, 3H). MS (ESI): mass calcd. forC₃₁H₄₂BNO₅ [M+AcO]− 578.33, found 578.4. HPLC: 99.0% (220 nm), 100.0%(254 nm).

Example 2 Antibacterial MIC Assays

All MIC testing of bacteria followed the Clinical and LaboratoryStandards Institute (CLSI) guidelines for antimicrobial testing ofaerobic bacteria (Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria that Grow Aerobically; Approved Standard—TenthEdition, M07-A10; Performance Standards for Antimicrobial SusceptibilityTesting; Twenty-fifth Informational Supplement, M100-S25).

Briefly, the microbroth dilution MIC method was used to quantitativelymeasure the in vitro antibacterial activity of a compound against agiven bacterial isolate. The following bacterial strains were evaluated:Staphylococcus aureus, MRSA (ATCC 33591) and Streptococcus pneumoniae(ATCC 49619). Bacteria were grown in cation-adjusted Mueller-Hintonbroth, with additions as required per species growth requirements (e.g.3% lysed horse blood for fastidious organisms such as S. pneumoniae). Adirect colony suspension in saline was prepared from colonies on anovernight agar plate to achieve a turbidity equivalent to 0.5 McFarlandstandard, which was subsequently diluted into the assay plate to achieve5×10⁵ CFU/mL. Assays plates were prepared by 2-fold dilution of compoundacross the plate and included a positive growth control. Afterincubation at 35° C. for 16-20 hours, the MIC was determined as thelowest concentration of compound that inhibits growth of the bacteria asdetected by the unaided eye.

Anti-Wolbachia High-Content Assay

C_(6/36) cells (ECACC #89051705, derived from Aedes albopictus larvae)were infected with Wolbachia pipientis derived from the supernatant ofcultured A. albopictus Aa23 cells to create a stably Wolbachia-infectedcell line C_(6/36) (wAlbB). This cell line was subpassaged 6-8 daysprior to plating out at a density of 2000 viable cells per well in a384-well CellCarrier plate suspended in Liebovitz media supplementedwith 20% fetal bovine serum, 2% tryptose phosphate broth and 1%non-essential amino acids. Compounds were dissolved and diluted in DMSO,and compound solution was added to each well to provide a final DMSOconcentration<1% and a total volume of 100 μL per well.

Following 7 days of sterile incubation at 26° C., staining mediacontaining SYTO 11 DNA dye was added to each well. After 15 minutes, allmedia was removed from each well and fresh media (no stain) was added.Imaging of each well was accomplished using a Perkin Elmer Operettahigh-content imaging system. Five fields per well were imaged using aconfocal 60× objective with the Fluorescein filter (excitation filter:460-490 nm; emission filter: 500-550 nm). Images were analyzed using thePerkin Elmer Harmony software to score each intact cell on the basis oftexture complexity of the cytoplasm. Full details can be found in:Clare, R. H. et al, J. Biomol. Screening, 2015, 20, 64-49.

Compound sample wells were analyzed and normalized (along with thepositive controls) against the vehicle (untreated) control to give apercentage reduction of Wolbachia-infected cells. Using the cell numberanalysis, compounds with a host cell number amounting to less than 50%of the vehicle control were classified as toxic and retested at areduced compound concentration. Dose-response curves were generated withpercentage reduction of Wolbachia-infected cells versus compoundconcentration, using 5-10 compound serial dilutions. Data were analyzedand compound EC₅₀s determined using a 4 parameter logistic nonlinearregression model. EC₅₀ is defined as the compound concentrationproducing a 50% reduction of Wolbachia in the C6/36 cell line.

Antibacterial testing results for exemplary compounds of the inventionare provided below. Units for MIC are μg/mL. Units for EC₅₀ are μM. MICof ≤0.25 is A, 0.5-2 is B, 4-32 is C, and ≥64 is D.

MIC MIC EC50 Com- Staphylococcus Streptococcus Wolbachia pound aureus,MRSA pneumoniae pipientis in C6/36 # (ATCC 33591) (ATCC 49619) cellline 1. A A 0.006 2. A B 0.015 3. A A 0.008 4. A B 0.158 5. A A 6. A B0.032 7. B C 0.428 8. A B 0.05 9. A B 0.052 10. A A 0.011 11. A A 0.112. A A 0.064 13. A B 0.081 14. A B 15. A A 16. A 17. B A 0.623 18. B >119. A B 0.215 20. A B >1 21. B A 0.104 22. B B >1 23. B B 0.613 24. AB >1 25. B B >1 26. A B >1 27. A A 0.027 28. B B >1 29. B B >1 30. BC >1 31. B B 0.197 32. A B >1 33. A B 0.149 34. A B 0.298 35. A B 0.0336. A B 0.193 37. A B 0.052 38. A B 0.009 39. A B 0.084 40. A B 0.01841. B B 0.625 42. C 43. B B 0.101 44. A B >1 45. A B 0.005 46. A B 0.02347. B C 0.303 49. B >1 49. B B 0.257 50. B A 0.409 51. A B >1 52. B B0.228 53. C B >1 54. A B 0.106 55. B B 56. A B 0.012 57. A B 0.113 58. AB 0.056 59. B C >1 60. B C >1 61. A A 0.123 62. A B 63. B C 64. A B 65.A B 66. B C 67. A B 68. A B 69. A A >1 70. B A 0.012 71. A A 0.001 72. AA 0.003 73. A A 0.001 74. A A 0.004 75. A B 0.009 76. B B >1 77. C B >178. B B 0.013 79. B B 0.056 80. A B 0.239 81. A A 0.034 82. B A 0.03683. A A 0.015 84. B B 0.078 85. A A 0.172 86. A B 0.001 87. A A 0.00488. A B 0.004 89. A A 0.107 90. A B 0.003 91. A B 0.001 92. A B 0.00393. A B 0.164 94. A B 0.026 95. A A 0.046 96. A B 0.014 97. A B 0.32998. B B 0.063 99. B B 0.013 100. D >1 101. B C >1 102. D D >1 103. A A0.419 104. A B

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound, or a salt or a hydrate or a solvatethereof, having a structure which is:

wherein X is H or F or OH; Y is selected from the group consisting of abond, —O—, —S—, —NH—, substituted or unsubstituted alkylene, andsubstituted or unsubstituted heteroalkylene; and Z is a substituted orunsubstituted heterocyclic ring or ring system containing at least oneendocyclic boron.
 2. The compound of claim 1, or a salt or a hydrate ora solvate thereof, wherein said Y is *—OCH₂— or *—SCH₂— or *—NHCH₂— or*—CH₂NH— or *—C(O)NH—, wherein * represents the point of attachment tosaid Z.
 3. The compound of claim 2, or a salt or a hydrate or a solvatethereof, wherein said Z is selected from the group consisting ofsubstituted or unsubstituted benzoxaborole, substituted or unsubstitutedpyridinyloxaborole, substituted or unsubstituted benzoxaborininol,substituted or unsubstituted benzoxazaborininol, substituted orunsubstituted benzodiazaborininol, substituted or unsubstitutedoxaborole, and substituted or unsubstituted dihydrobenzoazaborinine. 4.The compound of claim 3, or a salt or a hydrate or a solvate thereof,wherein said Z is

wherein R³, R^(3a), R⁴, R⁵, and R⁷ are each independently selected fromthe group consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ whereinR¹⁰ and R¹¹ are each independently selected from the group consisting ofH, halogen, cyano, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, and substituted or unsubstituted heteroaryl. 5.The compound of claim 3, or a salt or a hydrate or a solvate thereof,wherein said Z is

wherein R³, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.
 6. Thecompound of claim 3, or a salt or a hydrate or a solvate thereof,wherein said Z is

wherein R¹, R⁴, R⁵, and R⁷ are each independently selected from thegroup consisting of R¹⁰, —OR¹⁰, —NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰,—S(O)₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(O)OR¹⁰, and —C(O)NR¹⁰R¹¹ wherein R¹⁰ and R¹¹are each independently selected from the group consisting of H, halogen,cyano, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.
 7. Acombination comprising the compound of claim 1, or a pharmaceuticallyacceptable salt or a hydrate or a solvate thereof, together with atleast one other therapeutically active agent.
 8. The combination ofclaim 7, or a pharmaceutically acceptable salt or a hydrate or a solvatethereof, wherein the other therapeutically active agent is ananti-bacterial agent.
 9. A pharmaceutical formulation comprising: a) thecompound of claim 1, or a pharmaceutically acceptable salt or a hydrateor a solvate thereof, and b) a pharmaceutically acceptable excipient.10. The pharmaceutical formulation of claim 9, which is an oralformulation or an intravenous formulation.
 11. A method of inhibitingprotein synthesis in a bacteria, the method comprising contacting thebacteria with the compound of claim 1, or a pharmaceutically acceptablesalt or a hydrate or a solvate thereof, thereby inhibiting proteinsynthesis in the bacteria.
 12. A method of inhibiting the growth ofand/or killing a bacteria, the method comprising contacting the bacteriawith the compound of claim 1, or a pharmaceutically acceptable salt or ahydrate or a solvate thereof, thereby inhibiting the growth of and/orkilling the bacteria.
 13. The method of claim 11, wherein the bacteriais Gram-positive.
 14. The method of claim 11, wherein the bacteria isselected from the group consisting of Staphylococcus aureus,Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus,Wolbachia pipientis and bacteria of the Wolbachia genus.
 15. A method oftreating a disease in an animal, the method comprising administering tothe animal a therapeutically effective amount of the compound of claim1, or a pharmaceutically acceptable salt or a hydrate or a solvatethereof, thereby treating the disease.
 16. The method of claim 15,wherein the disease is associated with a Gram-positive bacteria.
 17. Themethod of claim 15, wherein the disease is selected from the groupconsisting of pneumonia, hospital-acquired pneumonia,hospital-associated pneumonia, community-acquired pneumonia, acutebacterial skin and skin-structure infection (ABSSSI), bacteremia,endocarditis, osteomyelitis, gastroenteritis, toxic shock syndrome,meningitis, septic arthritis, urinary tract infection, skin andskin-structure infection, strep throat, necrotizing fasciitis, otitismedia, sinusitis, actinomycosis, diptheria, anthrax, food poisoning,botulism, tetanus, gas gangrene, diarrhea, tuberculosis, leprosy,candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis,histoplasmosis, blastomycosis, paracoccidioidomycosis, zygomycosis,phaeohyphomycosis, rhinosporidiosis, enterobiasis, filariasis, lymphaticfilariasis, bancroftian filariasis, subcutaneous filariasis, seriouscavity filariasis, elephantiasis, elephantiasis tropica, lymphadenitis,lymphangitis, lymphedema, and onchocerciasis.
 18. The method of claim12, wherein the bacteria is Gram-positive.
 19. The method of claim 12,wherein the bacteria is selected from the group consisting ofStaphylococcus aureus, Streptococcus pneumoniae, methicillin-resistantStaphylococcus aureus, Wolbachia pipientis and bacteria of the Wolbachiagenus.